Genetic Variant CALHM1:p.Met323Ile (chr10-103455334-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001001412.4(CALHM1):c.969G>A(p.Met323Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 1,613,582 control chromosomes in the GnomAD database, including 446 homozygotes. 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.

Frequency

Genomes: 𝑓 0.017 ( 21 hom., cov: 34)

Exomes 𝑓: 0.022 ( 425 hom. )

Consequence

CALHM1
NM_001001412.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.275

Publications

9 publications found

Variant links:

COSMIC-nc: COSV107291560

Genes affected

CALHM1 (HGNC:23494): (calcium homeostasis modulator 1) This gene encodes a calcium channel that plays a role in processing of amyloid-beta precursor protein. A polymorphism at this locus has been reported to be associated with susceptibility to late-onset Alzheimer's disease in some populations, but the pathogenicity of this polymorphism is unclear.[provided by RefSeq, Mar 2010]

CALHM1 links:

ENSG00000234699 (HGNC:):

ENSG00000234699 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028559566).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0166 (2522/152380) while in subpopulation NFE AF = 0.0253 (1721/68040). AF 95% confidence interval is 0.0243. There are 21 homozygotes in GnomAd4. There are 1162 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALHM1	NM_001001412.4 link	c.969G>A	p.Met323Ile	missense_variant	Exon 2 of 2	ENST00000329905.6	NP_001001412.3	Q8IU99
LOC124902494	XR_007062275.1 link	n.794+2098C>T		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALHM1	ENST00000329905.6 link	c.969G>A	p.Met323Ile	missense_variant	Exon 2 of 2	1	NM_001001412.4	ENSP00000329926.6		Q8IU99
ENSG00000234699	ENST00000411906.2 link	n.1170+2098C>T		intron_variant	Intron 1 of 1	2

Frequencies

GnomAD3 genomes

AF:

0.0166

AC:

2520

AN:

152262

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00702

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0133

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.0130

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0253

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0160

AC:

4000

AN:

249428

AF XY:

0.0159

show subpopulations

Gnomad AFR exome

AF:

0.00623

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.00860

Gnomad EAS exome

AF:

0.000218

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0244

Gnomad OTH exome

AF:

0.0212

GnomAD4 exome

AF:

0.0223

AC:

32545

AN:

1461202

Hom.:

425

Cov.:

AF XY:

0.0218

AC XY:

15820

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.00606

AC:

203

AN:

33478

American (AMR)

AF:

0.0112

AC:

501

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00724

AC:

189

AN:

26116

East Asian (EAS)

AF:

0.000126

AC:

AN:

39700

South Asian (SAS)

AF:

0.00943

AC:

813

AN:

86230

European-Finnish (FIN)

AF:

0.0149

AC:

790

AN:

52882

Middle Eastern (MID)

AF:

0.0125

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0259

AC:

28745

AN:

1111944

Other (OTH)

AF:

0.0203

AC:

1227

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2125

4250

6376

8501

10626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1060

2120

3180

4240

5300

<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:

0.0166

AC:

2522

AN:

152380

Hom.:

Cov.:

AF XY:

0.0156

AC XY:

1162

AN XY:

74522

show subpopulations

African (AFR)

AF:

0.00702

AC:

292

AN:

41592

American (AMR)

AF:

0.0133

AC:

204

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00950

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5190

South Asian (SAS)

AF:

0.0118

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.0130

AC:

138

AN:

10628

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0253

AC:

1721

AN:

68040

Other (OTH)

AF:

0.0175

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

140

280

421

561

701

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0218

Hom.:

136

Bravo

AF:

0.0153

TwinsUK

AF:

0.0251

AC:

ALSPAC

AF:

0.0246

AC:

ESP6500AA

AF:

0.00817

AC:

ESP6500EA

AF:

0.0200

AC:

172

ExAC

AF:

0.0169

AC:

2049

Asia WGS

AF:

0.00606

AC:

AN:

3478

EpiCase

AF:

0.0238

EpiControl

AF:

0.0240

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.81

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.010

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.55

MetaRNN

Benign

0.0029

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PhyloP100

-0.28

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.33

REVEL

Benign

0.14

Sift

Benign

0.42

Sift4G

Benign

0.50

Polyphen

0.0

Vest4

0.019

MutPred

0.30

Loss of disorder (P = 0.0511);

MPC

0.17

ClinPred

0.0042

GERP RS

3.7

Varity_R

0.22

gMVP

0.18

Mutation Taster

=100/0

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over