Genetic Variant CALHM3:p.Arg257Gly (chr10-103473479-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_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. 16/22 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

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.325

Publications

0 publications found

Variant links:

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]

CALHM3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -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 rank	MANE	Protein	UniProt
CALHM3	NM_001129742.2 link	c.769C>G	p.Arg257Gly	missense_variant	Exon 3 of 3	ENST00000369783.4	NP_001123214.1	Q86XJ0

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM3	ENST00000369783.4 link	c.769C>G	p.Arg257Gly	missense_variant	Exon 3 of 3	1	NM_001129742.2	ENSP00000358798.4		Q86XJ0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396724

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688724

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31546

American (AMR)

AF:

0.00

AC:

AN:

35590

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25038

East Asian (EAS)

AF:

0.00

AC:

AN:

35700

South Asian (SAS)

AF:

0.00

AC:

AN:

79038

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48578

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5694

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1077624

Other (OTH)

AF:

0.00

AC:

AN:

57916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 06, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.51

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0073

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.90

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.59

M_CAP

Benign

0.0069

MetaRNN

Benign

0.054

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.55

PhyloP100

0.33

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

REVEL

Benign

0.060

Sift

Benign

0.097

Sift4G

Benign

0.30

Vest4

0.11

MutPred

0.30

Loss of MoRF binding (P = 0.0194);

MVP

0.13

ClinPred

0.085

GERP RS

3.6

Varity_R

0.091

gMVP

0.33

Mutation Taster

=98/2

polymorphism

(source)

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

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10-103473479-G-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over