rs2232659

Positions:

• chr10-103449656-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_015916.5(CALHM2):​c.286G>A​(p.Ala96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,613,810 control chromosomes in the GnomAD database, including 468 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 0.017 (41 hom., cov: 32)
  • Exomes 𝑓: 0.020 (427 hom.)
• Consequence: CALHM2 NM_015916.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.86

Genes affected

CALHM2 (HGNC:23493): (calcium homeostasis modulator family member 2) Predicted to enable cation channel activity. Involved in positive regulation of apoptotic process. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CALHM2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0025753677).
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0168 (2564/152324) while in subpopulation SAS AF= 0.0201 (97/4830). AF 95% confidence interval is 0.019. There are 41 homozygotes in gnomad4. There are 1374 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 41 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALHM2	NM_015916.5	c.286G>A	p.Ala96Thr	missense_variant	3/4	ENST00000260743.10	NP_057000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALHM2	ENST00000260743.10	c.286G>A	p.Ala96Thr	missense_variant	3/4	1	NM_015916.5	ENSP00000260743.5
CALHM2	ENST00000369788.7	c.286G>A	p.Ala96Thr	missense_variant	3/4	2		ENSP00000358803.3
CALHM2	ENST00000494180.1	n.934G>A		non_coding_transcript_exon_variant	2/2	2
CALHM2	ENST00000463878.1	n.*43G>A		downstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0169 AC: 2565 AN: 152206 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.00265

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0147

Gnomad ASJ AF: 0.0317

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0201

Gnomad FIN AF: 0.0586

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0199

Gnomad OTH AF: 0.0172

GnomAD3 exomes AF: 0.0217 AC: 5462 AN: 251274 Hom.: 127 AF XY: 0.0225 AC XY: 3061 AN XY: 135888

Gnomad AFR exome AF: 0.00283

Gnomad AMR exome AF: 0.00916

Gnomad ASJ exome AF: 0.0316

Gnomad EAS exome AF: 0.000761

Gnomad SAS exome AF: 0.0203

Gnomad FIN exome AF: 0.0641

Gnomad NFE exome AF: 0.0229

Gnomad OTH exome AF: 0.0253

GnomAD4 exome AF: 0.0198 AC: 28995 AN: 1461486 Hom.: 427 Cov.: 32 AF XY: 0.0201 AC XY: 14609 AN XY: 727062

Gnomad4 AFR exome AF: 0.00349

Gnomad4 AMR exome AF: 0.00872

Gnomad4 ASJ exome AF: 0.0328

Gnomad4 EAS exome AF: 0.000151

Gnomad4 SAS exome AF: 0.0208

Gnomad4 FIN exome AF: 0.0626

Gnomad4 NFE exome AF: 0.0190

Gnomad4 OTH exome AF: 0.0198

GnomAD4 genome AF: 0.0168 AC: 2564 AN: 152324 Hom.: 41 Cov.: 32 AF XY: 0.0184 AC XY: 1374 AN XY: 74482

Gnomad4 AFR AF: 0.00265

Gnomad4 AMR AF: 0.0146

Gnomad4 ASJ AF: 0.0317

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0201

Gnomad4 FIN AF: 0.0586

Gnomad4 NFE AF: 0.0199

Gnomad4 OTH AF: 0.0170

Alfa AF: 0.0194 Hom.: 56

Bravo AF: 0.0126

TwinsUK AF: 0.0173 AC: 64

ALSPAC AF: 0.0169 AC: 65

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0195 AC: 168

ExAC AF: 0.0212 AC: 2577

Asia WGS AF: 0.00779 AC: 28 AN: 3478

EpiCase AF: 0.0219

EpiControl AF: 0.0213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.63	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	19
DANN	Uncertain	0.98
DEOGEN2	Benign	0.010	T;T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.042
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.77	.;T
MetaRNN	Benign	0.0026	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.7	L;L
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.031
Sift	Benign	0.47	T;T
Sift4G	Benign	0.61	T;T
Polyphen		0.010	B;B
Vest4		0.13
MPC		0.21
ClinPred		0.014	T
GERP RS		5.5
Varity_R		0.069
gMVP		0.50

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: rs2232659; hg19: chr10-105209413; COSMIC: COSV53298490; COSMIC: COSV53298490;