Genetic Variant CALHM6:p.Arg73Cys (chr6-116462146-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001010919.3(CALHM6):c.217C>T(p.Arg73Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000145 in 1,378,424 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R73G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

CALHM6
NM_001010919.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.25

Publications

0 publications found

Variant links:

Genes affected

CALHM6 (HGNC:33391): (calcium homeostasis modulator family member 6) 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]

CALHM6 links:

ENSG00000285446 (HGNC:):

ENSG00000285446 links:

CALHM6-AS1 (HGNC:40971): (CALHM6 antisense RNA 1)

CALHM6-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001010919.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALHM6	NM_001010919.3	MANE Select	c.217C>T	p.Arg73Cys	missense	Exon 2 of 3	NP_001010919.1	Q5R3K3-1
CALHM6	NM_001276460.2		c.9+717C>T		intron	N/A	NP_001263389.1	Q5R3K3-2
CALHM6-AS1	NR_174951.1		n.87-952G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALHM6	ENST00000368605.3	TSL:5 MANE Select	c.217C>T	p.Arg73Cys	missense	Exon 2 of 3	ENSP00000357594.1	Q5R3K3-1
ENSG00000285446	ENST00000644499.1		c.767-1137C>T		intron	N/A	ENSP00000495266.1	A0A2R8Y6J1
CALHM6	ENST00000859968.1		c.217C>T	p.Arg73Cys	missense	Exon 1 of 2	ENSP00000530027.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1378424

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

680096

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

30894

American (AMR)

AF:

0.00

AC:

AN:

35410

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24972

East Asian (EAS)

AF:

0.00

AC:

AN:

35168

South Asian (SAS)

AF:

0.0000127

AC:

AN:

78710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

37290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4892

European-Non Finnish (NFE)

AF:

9.31e-7

AC:

AN:

1073624

Other (OTH)

AF:

0.00

AC:

AN:

57464

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Uncertain

0.014

BayesDel_noAF

Benign

-0.22

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.072

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.84

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-0.95

PhyloP100

1.3

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.6

REVEL

Benign

0.20

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.47

MutPred

0.53

Loss of MoRF binding (P = 0.0311)

MVP

0.50

MPC

0.54

ClinPred

1.0

GERP RS

5.1

PromoterAI

0.0040

Neutral

(source)

Varity_R

0.48

gMVP

0.42

Mutation Taster

=83/17

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over