Variant 19-12940316-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_004343.4(CALR):c.566G>C(p.Ser189Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00151 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00086 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0016 ( 1 hom. )

Consequence

CALR
NM_004343.4 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 1.64

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:

CALR (HGNC:):

CALR links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.022202253).

BP6

Variant 19-12940316-G-C is Benign according to our data. Variant chr19-12940316-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 3046043.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High AC in GnomAd4 at 131 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALR	NM_004343.4 linkuse as main transcript	c.566G>C	p.Ser189Thr	missense_variant	5/9	ENST00000316448.10	NP_004334.1	P27797V9HW88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALR	ENST00000316448.10 linkuse as main transcript	c.566G>C	p.Ser189Thr	missense_variant	5/9	1	NM_004343.4	ENSP00000320866.4		P27797

Frequencies

GnomAD3 genomes

AF:

0.000861

AC:

131

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

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:

0.00159

Gnomad OTH

AF:

0.000956

GnomAD3 exomes

AF:

0.000839

AC:

211

AN:

251494

Hom.:

AF XY:

0.000750

AC XY:

102

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.000369

Gnomad AMR exome

AF:

0.000434

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.000185

Gnomad NFE exome

AF:

0.00159

Gnomad OTH exome

AF:

0.000651

GnomAD4 exome

AF:

0.00158

AC:

2305

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00153

AC XY:

1115

AN XY:

727246

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000335

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000580

Gnomad4 FIN exome

AF:

0.000168

Gnomad4 NFE exome

AF:

0.00199

Gnomad4 OTH exome

AF:

0.000894

GnomAD4 genome

AF:

0.000860

AC:

131

AN:

152318

Hom.:

Cov.:

AF XY:

0.000685

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00159

Gnomad4 OTH

AF:

0.000946

Alfa

AF:

0.00121

Hom.:

Bravo

AF:

0.000824

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00186

AC:

ExAC

AF:

0.000873

AC:

106

EpiCase

AF:

0.00131

EpiControl

AF:

0.00101

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

CALR-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 01, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-0.34

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.92

LIST_S2

Uncertain

0.87

D;D

M_CAP

Benign

0.014

MetaRNN

Benign

0.022

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

N;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.036

Sift

Benign

0.089

T;.

Sift4G

Benign

0.11

T;T

Polyphen

0.0020

B;.

Vest4

0.25

MVP

0.53

MPC

0.27

ClinPred

0.0092

GERP RS

3.1

Varity_R

0.11

gMVP

0.14

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

Details are displayed if max score is > 0.2

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