Genetic Variant CALHM6:p.Leu111His (chr6-116462261-T-A) – 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.332T>A(p.Leu111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000218 in 1,376,038 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. L111P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000016 ( 0 hom. )

Consequence

CALHM6
NM_001010919.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.39

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.332T>A	p.Leu111His	missense	Exon 2 of 3	NP_001010919.1	Q5R3K3-1
CALHM6	NM_001276460.2		c.9+832T>A		intron	N/A	NP_001263389.1	Q5R3K3-2
CALHM6-AS1	NR_174951.1		n.87-1067A>T		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALHM6	ENST00000368605.3	TSL:5 MANE Select	c.332T>A	p.Leu111His	missense	Exon 2 of 3	ENSP00000357594.1	Q5R3K3-1
ENSG00000285446	ENST00000644499.1		c.767-1022T>A		intron	N/A	ENSP00000495266.1	A0A2R8Y6J1
CALHM6	ENST00000859968.1		c.332T>A	p.Leu111His	missense	Exon 1 of 2	ENSP00000530027.1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.00

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00

AC:

AN:

12228

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000163

AC:

AN:

1223992

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

593658

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

24310

American (AMR)

AF:

0.00

AC:

AN:

12042

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17388

East Asian (EAS)

AF:

0.00

AC:

AN:

27388

South Asian (SAS)

AF:

0.00

AC:

AN:

54710

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29860

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3506

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1004272

Other (OTH)

AF:

0.0000396

AC:

AN:

50516

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

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

AF:

0.00000658

AC:

AN:

152046

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10586

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67986

Other (OTH)

AF:

0.000478

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Benign

-0.33

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.075

Eigen

Uncertain

0.26

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.58

M_CAP

Uncertain

0.19

MetaRNN

Uncertain

0.59

MetaSVM

Benign

-1.0

PhyloP100

1.4

PrimateAI

Pathogenic

0.82

PROVEAN

Pathogenic

-5.2

REVEL

Benign

0.27

Sift

Uncertain

0.0010

Sift4G

Pathogenic

0.0010

Polyphen

1.0

Vest4

0.54

MutPred

0.65

Loss of stability (P = 0.0499)

MVP

0.34

MPC

0.52

ClinPred

0.97

GERP RS

2.6

PromoterAI

0.0018

Neutral

(source)

Varity_R

0.50

gMVP

0.46

Mutation Taster

=81/19

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