CALR c.1194G>T, p.Glu398Asp

NM_004343.3:c.1194G>T
COSMIC ID: COSM1738023
Variant of Uncertain Significance (VUS)
The NM_004343.3:c.1194G>T variant in the CALR gene is classified as a Variant of Uncertain Significance (VUS). This classification is supported by the application of PM2 and BP4 criteria, indicating the variant is extremely rare and computational evidence suggests a benign impact. Additional evidence is needed to evaluate other criteria.
ACMG/AMP Criteria Applied
PM2 BP4

Genetic Information

Gene & Transcript Details
Gene
CALR
Transcript
NM_004343.4 MANE Select
Total Exons
9
Strand
Forward (+)
Reference Sequence
NC_000019.9
Alternative Transcripts
IDStatusDetails
NM_004343.3 RefSeq Select 9 exons | Forward
NM_004343.2 Alternative 9 exons | Forward
Variant Details
HGVS Notation
NM_004343.3:c.1194G>T
Protein Change
E398D
Location
Exon 9 (Exon 9 of 9)
9
5'Exon Structure (9 total)3'
Functional Consequence
Missense Variant
Related Variants
No evidence of other pathogenic variants at position 398 in gene CALR
Alternate Identifiers
COSM1738023
Variant interpretation based on transcript NM_004343.4

Genome Browser

UCSC Genome Browser hg19/GRCh37
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HGVS InputNM_004343:c.1194G>T
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Clinical Data

Population Frequency
Global Frequency
0.00638%
Rare
Highest in Population
African/African American
0.0115%
Low Frequency
Global: 0.00638%
African/African American: 0.0115%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 31356Alt: 2Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is rare in the population (0.006380% MAF).
ClinVar 2025-04-07T11:10:02.037728
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC
COSMIC ID
COSM1738023
Recurrence
2 occurrences
PM1 Criteria
Not Applied
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Functional Impact

Functional Domain
Hotspot Status
Not a hotspot
Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain
No evidence of other pathogenic variants at position 398 in gene CALR
Functional Studies & Therapeutic Relevance
Functional Summary
The variant CALR E398D has not been functionally characterized in the provided sources.

Computational Analysis

Pathogenicity Predictions
REVEL Score
0.109
0.109
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Unknown
PP3 Applied
No
SpliceAI Scores Window: ±500bp
Effect TypeScorePosition
-Acceptor Loss
0.0
-110 bp
-Donor Loss
0.0
-110 bp
+Acceptor Gain
0.0
-133 bp
+Donor Gain
0.0
-452 bp
High impact (≥0.5)
Medium impact (0.2-0.49)
Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)
PM2
PM2 (Moderate)
According to standard ACMG guidelines: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: The variant has a minor allele frequency (MAF) of 0.00638% in gnomAD, indicating it is extremely rare. Therefore, this criterion meets the requirements because the variant is absent from controls or present at a very low frequency.
BP4
BP4 (Supporting)
According to standard ACMG guidelines: 'BP4 – Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: The REVEL score is 0.11, which is below the threshold of 0.15, and SpliceAI analysis indicates no predicted impact on splicing. Therefore, this criterion meets the requirements because the computational evidence suggests a benign impact.