19-12939156-C-G

Variant names:

• chr19-12939156-C-G
• NM_004343.4:c.114C>G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004343.4(CALR):​c.114C>G​(p.Ile38Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALR NM_004343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.784

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALR	NM_004343.4	c.114C>G	p.Ile38Met	missense_variant	Exon 2 of 9	ENST00000316448.10	NP_004334.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALR	ENST00000316448.10	c.114C>G	p.Ile38Met	missense_variant	Exon 2 of 9	1	NM_004343.4	ENSP00000320866.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 03, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.114C>G (p.I38M) alteration is located in exon 2 (coding exon 2) of the CALR gene. This alteration results from a C to G substitution at nucleotide position 114, causing the isoleucine (I) at amino acid position 38 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.086	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.058	D
MetaRNN	Uncertain	0.56	D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Pathogenic	3.3	M;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-2.0	N;.
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;.
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.95	P;.
Vest4		0.14
MutPred		0.76		Gain of disorder (P = 0.0434);Gain of disorder (P = 0.0434);
MVP		0.72
MPC		0.88
ClinPred		0.99	D
GERP RS		-4.3
Varity_R		0.32
gMVP		0.67

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13049970;