dbSNP rs1555760738: CALR:p.Leu367ThrfsTer46 (chr19-12943750-AGCAGAGGCTTAAGGAGGAGGAAGAAGACAAGAAACGCAAAGAGGAGGAGGAG-A) – ACMG Classification: Likely_pathogenic (8 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 12P and 4B. PVS1_StrongPP5_Very_StrongBS2

The NM_004343.4(CALR):c.1099_1150delCTTAAGGAGGAGGAAGAAGACAAGAAACGCAAAGAGGAGGAGGAGGCAGAGG(p.Leu367ThrfsTer46) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000301 in 1,460,220 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

CALR
NM_004343.4 frameshift

Scores

Not classified

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4O:4

Conservation

PhyloP100: 8.15

Variant links:

Genes affected

CALR (HGNC:1455): (calreticulin) Calreticulin is a highly conserved chaperone protein which resides primarily in the endoplasmic reticulum, and is involved in a variety of cellular processes, among them, cell adhesion. Additionally, it functions in protein folding quality control and calcium homeostasis. Calreticulin is also found in the nucleus, suggesting that it may have a role in transcription regulation. Systemic lupus erythematosus is associated with increased autoantibody titers against calreticulin. Recurrent mutations in calreticulin have been linked to various neoplasms, including the myeloproliferative type.[provided by RefSeq, May 2020]

CALR links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.124 CDS is truncated, and there are 0 pathogenic variants in the truncated region.

PP5

Variant 19-12943750-AGCAGAGGCTTAAGGAGGAGGAAGAAGACAAGAAACGCAAAGAGGAGGAGGAG-A is Pathogenic according to our data. Variant chr19-12943750-AGCAGAGGCTTAAGGAGGAGGAAGAAGACAAGAAACGCAAAGAGGAGGAGGAG-A is described in ClinVar as [Pathogenic]. Clinvar id is 97006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALR	NM_004343.4 link	c.1099_1150delCTTAAGGAGGAGGAAGAAGACAAGAAACGCAAAGAGGAGGAGGAGGCAGAGG	p.Leu367ThrfsTer46	frameshift_variant	Exon 9 of 9	ENST00000316448.10	NP_004334.1	P27797V9HW88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALR	ENST00000316448.10 link	c.1099_1150delCTTAAGGAGGAGGAAGAAGACAAGAAACGCAAAGAGGAGGAGGAGGCAGAGG	p.Leu367ThrfsTer46	frameshift_variant	Exon 9 of 9	1	NM_004343.4	ENSP00000320866.4		P27797

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152176

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000301

AC:

AN:

1460220

Hom.:

AF XY:

0.0000441

AC XY:

AN XY:

726272

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.0000226

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000342

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4Other:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Essential thrombocythemia

Other:2

Jan 24, 2024

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Significance: -

Review Status: no assertion criteria provided

Collection Method: clinical testing

A large majority of myeloproliferative neoplasms with nonmutated JAK2 exhibit somatic CALR mutations. In a subset of such cases with essential thrombocythemia, 67% had CALR mutation. -

Jan 24, 2024

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Significance: -

Review Status: no assertion criteria provided

Collection Method: clinical testing

In a cohort of 1107 myeloproliferative neoplasm patients, those with "mutated CALR had a lower risk of thromobsis and longer overall survival than patients with mutated JAK2." -

Acute myeloid leukemia

Other:2

Jan 24, 2024

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Significance: -

Review Status: no assertion criteria provided

Collection Method: clinical testing

While there are strong associations of this variant to thrombocythemia and myeloproliferative neoplasms, its oncogenicity and clinical impact in this case of acute myeloid leukemia is uncertain because the allele frequency decreased over time from 11% (progressive thrombocythemia) to 3% (AML in remission) to undetectable at AML relapse. -

Jan 24, 2024

Molecular Diagnostics Laboratory, Fox Chase Cancer Center - Temple Health

Significance: -

Review Status: no assertion criteria provided

Collection Method: clinical testing

not provided

Pathogenic:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CALR: PS4, PVS1:Strong, PM2:Supporting -

Thrombocythemia 1

Pathogenic:1

Dec 19, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary myelofibrosis

Pathogenic:1

Dec 19, 2013

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Primary myelofibrosis;C3277671:Thrombocythemia 1

Pathogenic:1

Feb 10, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over