10-103473479-G-C

Position:

• chr10-103473479-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001129742.2(CALHM3):​c.769C>G​(p.Arg257Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CALHM3 NM_001129742.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.325

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.053866297).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CALHM3	NM_001129742.2	c.769C>G	p.Arg257Gly	missense_variant	3/3	ENST00000369783.4	NP_001123214.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CALHM3	ENST00000369783.4	c.769C>G	p.Arg257Gly	missense_variant	3/3	1	NM_001129742.2	ENSP00000358798	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396724 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 688724

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 06, 2024

The c.769C>G (p.R257G) alteration is located in exon 3 (coding exon 3) of the CALHM3 gene. This alteration results from a C to G substitution at nucleotide position 769, causing the arginine (R) at amino acid position 257 to be replaced by a glycine (G). 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	0.075
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	10
DANN	Benign	0.85
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0069	T
MetaRNN	Benign	0.054	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.55	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.060
Sift	Benign	0.097	T
Sift4G	Benign	0.30	T
Vest4		0.11
MutPred		0.30		Loss of MoRF binding (P = 0.0194);
MVP		0.13
ClinPred		0.085	T
GERP RS		3.6
Varity_R		0.091
gMVP		0.33

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: chr10-105233236;