chr19-16496092-A-G

Position:

• chr19-16496092-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145046.5(CALR3):​c.38T>C​(p.Met13Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,455,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CALR3 NM_145046.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.18

Genes affected

CALR3 (HGNC:20407): (calreticulin 3) The protein encoded by this gene belongs to the calreticulin family, members of which are calcium-binding chaperones localized mainly in the endoplasmic reticulum. This protein is also localized to the endoplasmic reticulum lumen, however, its capacity for calcium-binding may be absent or much lower than other family members. This gene is specifically expressed in the testis, and may be required for sperm fertility. Mutation in this gene has been associated with familial hypertrophic cardiomyopathy. [provided by RefSeq, Dec 2011]

ENSG00000141979 (HGNC:):

ACMG classification

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=0.124340534).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALR3	NM_145046.5	c.38T>C	p.Met13Thr	missense_variant	1/9	ENST00000269881.8	NP_659483.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALR3	ENST00000269881.8	c.38T>C	p.Met13Thr	missense_variant	1/9	1	NM_145046.5	ENSP00000269881.3
ENSG00000141979	ENST00000409035.1	n.*380-240T>C		intron_variant		2		ENSP00000386951.2
CALR3	ENST00000600762.1	c.26T>C	p.Met9Thr	missense_variant	1/4	3		ENSP00000471533.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455206 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 723262

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypertrophic cardiomyopathy 19 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 05, 2016

Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. In summary, this is a novel missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. It has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a CALR3-related disease. This sequence change replaces methionine with threonine at codon 13 of the CALR3 protein (p.Met13Thr). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and threonine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	12
DANN	Benign	0.78
DEOGEN2	Benign	0.067	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.070	N
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.49	N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.080
Sift	Benign	0.19	T
Sift4G	Benign	0.090	T
Polyphen		0.026	B
Vest4		0.12
MutPred		0.56		Loss of helix (P = 0.0444);
MVP		0.18
MPC		0.17
ClinPred		0.10	T
GERP RS		1.9
Varity_R		0.33
gMVP		0.32

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

Other links and lift over

dbSNP: rs878855223; hg19: chr19-16606903;