10-103473353-C-T

Variant names:

• chr10-103473353-C-T
• rs2986035
• NM_001129742.2:c.895G>A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001129742.2(CALHM3):​c.895G>A​(p.Asp299Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.758 in 1,500,634 control chromosomes in the GnomAD database, including 434,007 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/18 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: 𝑓 0.71 (39457 hom., cov: 32)
  • Exomes 𝑓: 0.76 (394550 hom.)
• Consequence: CALHM3 NM_001129742.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.34

Genes affected

CALHM3 (HGNC:23458): (calcium homeostasis modulator 3) Predicted to enable cation channel activity. Predicted to be involved in ATP transport. Predicted to be located in basolateral plasma membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.971287E-7).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.836 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM3	NM_001129742.2	c.895G>A	p.Asp299Asn	missense_variant	Exon 3 of 3	ENST00000369783.4	NP_001123214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM3	ENST00000369783.4	c.895G>A	p.Asp299Asn	missense_variant	Exon 3 of 3	1	NM_001129742.2	ENSP00000358798.4

Frequencies

GnomAD3 genomes AF: 0.715 AC: 108618 AN: 151964 Hom.: 39436 Cov.: 32

Gnomad AFR AF: 0.583

Gnomad AMI AF: 0.679

Gnomad AMR AF: 0.784

Gnomad ASJ AF: 0.738

Gnomad EAS AF: 0.790

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.790

Gnomad MID AF: 0.741

Gnomad NFE AF: 0.751

Gnomad OTH AF: 0.727

GnomAD3 exomes AF: 0.780 AC: 92797 AN: 118926 Hom.: 36460 AF XY: 0.786 AC XY: 48359 AN XY: 61548

Gnomad AFR exome AF: 0.590

Gnomad AMR exome AF: 0.830

Gnomad ASJ exome AF: 0.744

Gnomad EAS exome AF: 0.796

Gnomad SAS exome AF: 0.864

Gnomad FIN exome AF: 0.795

Gnomad NFE exome AF: 0.759

Gnomad OTH exome AF: 0.773

GnomAD4 exome AF: 0.763 AC: 1029443 AN: 1348552 Hom.: 394550 Cov.: 75 AF XY: 0.766 AC XY: 504240 AN XY: 658612

Gnomad4 AFR exome AF: 0.564

Gnomad4 AMR exome AF: 0.823

Gnomad4 ASJ exome AF: 0.744

Gnomad4 EAS exome AF: 0.811

Gnomad4 SAS exome AF: 0.859

Gnomad4 FIN exome AF: 0.789

Gnomad4 NFE exome AF: 0.759

Gnomad4 OTH exome AF: 0.760

GnomAD4 genome AF: 0.715 AC: 108684 AN: 152082 Hom.: 39457 Cov.: 32 AF XY: 0.720 AC XY: 53522 AN XY: 74352

Gnomad4 AFR AF: 0.583

Gnomad4 AMR AF: 0.785

Gnomad4 ASJ AF: 0.738

Gnomad4 EAS AF: 0.790

Gnomad4 SAS AF: 0.858

Gnomad4 FIN AF: 0.790

Gnomad4 NFE AF: 0.751

Gnomad4 OTH AF: 0.729

Alfa AF: 0.746 Hom.: 103632

Bravo AF: 0.708

TwinsUK AF: 0.758 AC: 2812

ALSPAC AF: 0.766 AC: 2952

ExAC AF: 0.736 AC: 16064

Asia WGS AF: 0.836 AC: 2908 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	15
DANN	Benign	0.72
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.72	T
MetaRNN	Benign	8.0e-7	T
MetaSVM	Benign	-1.0	T
PrimateAI	Benign	0.37	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.060
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.018
ClinPred		0.011	T
GERP RS		-0.34
Varity_R		0.079
gMVP		0.38

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: rs2986035; hg19: chr10-105233110; COSMIC: COSV63921815;