10-103447414-A-T

Variant summary

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

The NM_015916.5(CALHM2):c.710T>A(p.Val237Glu) 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. 12/21 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: CALHM2 NM_015916.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.52

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]

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=0.1604926).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CALHM2	NM_015916.5	c.710T>A	p.Val237Glu	missense_variant	4/4	ENST00000260743.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CALHM2	ENST00000260743.10	c.710T>A	p.Val237Glu	missense_variant	4/4	1	NM_015916.5	P1
CALHM2	ENST00000369788.7	c.710T>A	p.Val237Glu	missense_variant	4/4	2		P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 26, 2023

The c.710T>A (p.V237E) alteration is located in exon 4 (coding exon 2) of the CALHM2 gene. This alteration results from a T to A substitution at nucleotide position 710, causing the valine (V) at amino acid position 237 to be replaced by a glutamic acid (E). 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	Uncertain	0.38
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	22
Dann	Uncertain	0.98
DEOGEN2	Benign	0.0050	T;T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.072
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.16	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.27	N;N
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	2.3	N;N
REVEL	Benign	0.16
Sift	Benign	0.16	T;T
Sift4G	Uncertain	0.027	D;D
Polyphen		0.0	B;B
Vest4		0.40
MutPred		0.48		Gain of disorder (P = 0.0023);Gain of disorder (P = 0.0023);
MVP		0.22
MPC		0.58
ClinPred		0.57	D
GERP RS		5.4
Varity_R		0.31
gMVP		0.48

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: chr10-105207171;