CALR c.1194G>T, p.Glu398Asp
NM_004343.3:c.1194G>T
COSM1738023
Population Frequency
0.00638%
Low Frequency
ClinVar Classification
Unknown
0 publications
REVEL Score
0.109
Likely Benign
COSMIC Recurrence
2 occurrences
No Criteria Applied
Classification Evidence
Detailed Information
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
| ID | Status | Details |
|---|---|---|
| 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)
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
Clinical Evidence
Global Frequency
0.00638%
Rare
Highest in Population
African/African American
0.0115%
Low Frequency
Global: 0.00638%
African/African American: 0.0115%
0%
0.0005%
0.001%
0.01%
0.05%
1%+
Allele Information
Total: 31356
Alt: 2
Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is rare in the population (0.006380% MAF).
Classification
Unknown
Publications
0 publications
Clinical Statement
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
Summary
The variant CALR E398D has not been functionally characterized in the provided sources.
Computational Evidence
Pathogenicity Predictions
REVEL Score
0.109
0.109
Likely Benign
0.0
Uncertain (Low)
0.2
Uncertain (Med)
0.5
Likely Pathogenic
0.75
REVEL scores ≥ 0.75 are considered strong evidence of pathogenicity (PP3)
Predictor Consensus
Unknown
PP3 Applied
No
VCEP Guidelines
Applied ACMG/AMP Criteria
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.