19-16482726-G-C

Position:

• chr19-16482726-G-C

Variant summary

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

The NM_145046.5(CALR3):​c.738C>G​(p.Asp246Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin Lovd. Synonymous variant affecting the same amino acid position (i.e. D246D) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CALR3 NM_145046.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.20

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]

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/exons	MANE	UniProt
CALR3	NM_145046.5	c.738C>G	p.Asp246Glu	missense_variant	6/9	ENST00000269881.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALR3	ENST00000269881.8	c.738C>G	p.Asp246Glu	missense_variant	6/9	1	NM_145046.5	P1
CALR3	ENST00000602234.1	n.412C>G		non_coding_transcript_exon_variant	2/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 37

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.80
CADD	Benign	0.60
DANN	Benign	0.25
DEOGEN2	Benign	0.055	T
Eigen	Benign	-2.4
Eigen_PC	Benign	-2.3
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.055	T
M_CAP	Benign	0.0043	T
MetaRNN	Benign	0.055	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.6	N
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.3	N
REVEL	Benign	0.032
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.047
MutPred		0.47		Gain of helix (P = 0.1736);
MVP		0.10
MPC		0.14
ClinPred		0.052	T
GERP RS		-5.9
Varity_R		0.044
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.43		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.43		Position offset: 5

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: chr19-16593537;