dbSNP rs764831280: CALR:p.Thr34Asn (chr19-12939143-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004343.4(CALR):c.101C>A(p.Thr34Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CALR
NM_004343.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.173

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 Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09534472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALR	NM_004343.4 link	c.101C>A	p.Thr34Asn	missense_variant	Exon 2 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.101C>A	p.Thr34Asn	missense_variant	Exon 2 of 9	1	NM_004343.4	ENSP00000320866.4		P27797

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000419

AC:

AN:

238394

Hom.:

AF XY:

0.00000778

AC XY:

AN XY:

128582

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000348

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000138

AC:

AN:

1452998

Hom.:

Cov.:

AF XY:

0.00000277

AC XY:

AN XY:

721964

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000236

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.55

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.091

T;T

Eigen

Benign

-0.48

Eigen_PC

Benign

-0.39

FATHMM_MKL

Benign

0.26

LIST_S2

Uncertain

0.90

D;T

M_CAP

Benign

0.016

MetaRNN

Benign

0.095

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.81

L;.

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.13

N;.

REVEL

Benign

0.071

Sift

Benign

0.031

D;.

Sift4G

Benign

0.079

T;T

Polyphen

0.0

B;.

Vest4

0.34

MutPred

0.29

Gain of catalytic residue at T34 (P = 0.0118);Gain of catalytic residue at T34 (P = 0.0118);

MVP

0.43

MPC

0.33

ClinPred

0.18

GERP RS

3.9

RBP_binding_hub_radar

1.1

RBP_regulation_power_radar

3.3

Varity_R

0.11

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over