Genetic Variant CALHM3:p.Gly262Arg (chr10-103473464-C-G) – 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.784G>C(p.Gly262Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000292 in 1,539,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G262S) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

CALHM3
NM_001129742.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.727

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=0.05716616).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM3	NM_001129742.2 link	c.784G>C	p.Gly262Arg	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.784G>C	p.Gly262Arg	missense_variant	Exon 3 of 3	1	NM_001129742.2	ENSP00000358798.4		Q86XJ0

Frequencies

GnomAD3 genomes

AF:

0.0000335

AC:

AN:

149318

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000288

AC:

AN:

1390586

Hom.:

Cov.:

AF XY:

0.0000263

AC XY:

AN XY:

685258

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30520

American (AMR)

AF:

0.0000286

AC:

AN:

35002

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24646

East Asian (EAS)

AF:

0.00

AC:

AN:

35434

South Asian (SAS)

AF:

0.0000256

AC:

AN:

78052

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5660

European-Non Finnish (NFE)

AF:

0.0000307

AC:

AN:

1075314

Other (OTH)

AF:

0.0000695

AC:

AN:

57588

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000335

AC:

AN:

149318

Hom.:

Cov.:

AF XY:

0.0000549

AC XY:

AN XY:

72910

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

38908

American (AMR)

AF:

0.0000660

AC:

AN:

15148

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3464

East Asian (EAS)

AF:

0.00

AC:

AN:

5050

South Asian (SAS)

AF:

0.00

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000588

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2072

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000189

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.77

CADD

Benign

4.3

(source)

DANN

Benign

0.42

DEOGEN2

Benign

0.0075

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.32

M_CAP

Benign

0.0092

MetaRNN

Benign

0.057

MetaSVM

Benign

-0.98

MutationAssessor

Benign

0.0

PhyloP100

0.73

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.36

REVEL

Benign

0.020

Sift

Benign

0.34

Sift4G

Benign

0.53

Vest4

0.075

MutPred

0.25

Gain of MoRF binding (P = 0.0468);

MVP

0.25

ClinPred

0.078

GERP RS

2.6

Varity_R

0.039

gMVP

0.19

Mutation Taster

=100/0

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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10-103473464-C-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over