Genetic Variant NM_001366078.2:c.805T>C (chr6-116558071-T-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_001366078.2(CALHM4):c.805T>C(p.Cys269Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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. C269G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CALHM4
NM_001366078.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.839

Publications

1 publications found

Variant links:

Genes affected

CALHM4 (HGNC:21094): (calcium homeostasis modulator family member 4) Predicted to enable cation channel activity. Predicted to be involved in cation transmembrane transport. Predicted to be integral component of membrane. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CALHM4 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=0.04834056).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001366078.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALHM4	NM_001366078.2	MANE Select	c.805T>C	p.Cys269Arg	missense	Exon 2 of 2	NP_001353007.1	Q5JW98-1
CALHM4	NM_001256887.3		c.376T>C	p.Cys126Arg	missense	Exon 4 of 4	NP_001243816.1	Q5JW98-3
CALHM4	NM_001256888.3		c.373T>C	p.Cys125Arg	missense	Exon 4 of 4	NP_001243817.1	Q5JW98-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALHM4	ENST00000368596.4	TSL:5 MANE Select	c.805T>C	p.Cys269Arg	missense	Exon 2 of 2	ENSP00000357585.3	Q5JW98-1
CALHM4	ENST00000405399.5	TSL:1	c.376T>C	p.Cys126Arg	missense	Exon 4 of 4	ENSP00000385836.1	Q5JW98-3
CALHM4	ENST00000368597.6	TSL:1	c.247T>C	p.Cys83Arg	missense	Exon 3 of 3	ENSP00000357586.2	Q5JW98-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461866

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111990

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.17

BayesDel_noAF

Benign

-0.49

CADD

Benign

(source)

DANN

Benign

0.67

DEOGEN2

Benign

0.0089

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.14

LIST_S2

Benign

0.55

M_CAP

Benign

0.0041

MetaRNN

Benign

0.048

MetaSVM

Benign

-1.0

PhyloP100

0.84

PrimateAI

Benign

0.48

PROVEAN

Benign

-1.3

REVEL

Benign

0.056

Sift

Benign

0.55

Sift4G

Benign

0.89

Polyphen

0.091

Vest4

0.26

MutPred

0.43

Gain of disorder (P = 0.0188)

MVP

0.081

MPC

0.20

ClinPred

0.094

GERP RS

0.48

Varity_R

0.37

gMVP

0.19

Mutation Taster

=95/5

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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over