10-103449529-G-A

Variant names:

• chr10-103449529-G-A
• NM_015916.5:c.413C>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_015916.5(CALHM2):​c.413C>T​(p.Pro138Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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: 8.66

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3449198).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM2	NM_015916.5	c.413C>T	p.Pro138Leu	missense_variant	Exon 3 of 4	ENST00000260743.10	NP_057000.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM2	ENST00000260743.10	c.413C>T	p.Pro138Leu	missense_variant	Exon 3 of 4	1	NM_015916.5	ENSP00000260743.5
CALHM2	ENST00000369788.7	c.413C>T	p.Pro138Leu	missense_variant	Exon 3 of 4	2		ENSP00000358803.3
CALHM2	ENST00000463878.1	n.*170C>T		downstream_gene_variant		3
CALHM2	ENST00000494180.1	n.*96C>T		downstream_gene_variant		2

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

Sep 15, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.413C>T (p.P138L) alteration is located in exon 3 (coding exon 1) of the CALHM2 gene. This alteration results from a C to T substitution at nucleotide position 413, causing the proline (P) at amino acid position 138 to be replaced by a leucine (L). 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	Benign	0.19
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.015	T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	.;D
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.34	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.9	N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T
Sift4G	Benign	0.81	T;T
Polyphen		0.11	B;B
Vest4		0.66
MutPred		0.40		Loss of disorder (P = 0.0389);Loss of disorder (P = 0.0389);
MVP		0.34
MPC		0.79
ClinPred		0.94	D
GERP RS		5.3
Varity_R		0.31
gMVP		0.73

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: chr10-105209286;