Genetic Variant CALHM1:p.Leu86Pro (chr10-103458495-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001001412.4(CALHM1):c.257T>C(p.Leu86Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.757 in 1,612,874 control chromosomes in the GnomAD database, including 466,030 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 0.80 ( 49593 hom., cov: 33)

Exomes 𝑓: 0.75 ( 416437 hom. )

Consequence

CALHM1
NM_001001412.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.156

Publications

103 publications found

Variant links:

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=8.984875E-7).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.921 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001001412.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM1	NM_001001412.4	MANE Select	c.257T>C	p.Leu86Pro	missense	Exon 1 of 2	NP_001001412.3	Q8IU99

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CALHM1	ENST00000329905.6	TSL:1 MANE Select	c.257T>C	p.Leu86Pro	missense	Exon 1 of 2	ENSP00000329926.6	Q8IU99
	ENSG00000234699	ENST00000411906.2	TSL:2	n.1171-3935A>G		intron	N/A

Frequencies

GnomAD3 genomes

AF:

0.803

AC:

122013

AN:

152016

Hom.:

49542

Cov.:

show subpopulations

Gnomad AFR

AF:

0.929

Gnomad AMI

AF:

0.644

Gnomad AMR

AF:

0.796

Gnomad ASJ

AF:

0.730

Gnomad EAS

AF:

0.888

Gnomad SAS

AF:

0.863

Gnomad FIN

AF:

0.795

Gnomad MID

AF:

0.737

Gnomad NFE

AF:

0.724

Gnomad OTH

AF:

0.782

GnomAD2 exomes

AF:

0.789

AC:

195046

AN:

247100

AF XY:

0.787

show subpopulations

Gnomad AFR exome

AF:

0.936

Gnomad AMR exome

AF:

0.837

Gnomad ASJ exome

AF:

0.740

Gnomad EAS exome

AF:

0.884

Gnomad FIN exome

AF:

0.792

Gnomad NFE exome

AF:

0.724

Gnomad OTH exome

AF:

0.761

GnomAD4 exome

AF:

0.753

AC:

1099252

AN:

1460740

Hom.:

416437

Cov.:

AF XY:

0.754

AC XY:

548004

AN XY:

726694

show subpopulations

African (AFR)

AF:

0.936

AC:

31350

AN:

33478

American (AMR)

AF:

0.833

AC:

37213

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.740

AC:

19330

AN:

26110

East Asian (EAS)

AF:

0.917

AC:

36395

AN:

39690

South Asian (SAS)

AF:

0.864

AC:

74487

AN:

86250

European-Finnish (FIN)

AF:

0.790

AC:

41472

AN:

52524

Middle Eastern (MID)

AF:

0.735

AC:

4242

AN:

5768

European-Non Finnish (NFE)

AF:

0.727

AC:

808531

AN:

1111866

Other (OTH)

AF:

0.766

AC:

46232

AN:

60358

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

18247

36493

54740

72986

91233

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20180

40360

60540

80720

100900

<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:

0.803

AC:

122124

AN:

152134

Hom.:

49593

Cov.:

AF XY:

0.807

AC XY:

59990

AN XY:

74372

show subpopulations

African (AFR)

AF:

0.929

AC:

38587

AN:

41558

American (AMR)

AF:

0.796

AC:

12177

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.730

AC:

2533

AN:

3470

East Asian (EAS)

AF:

0.889

AC:

4569

AN:

5142

South Asian (SAS)

AF:

0.863

AC:

4160

AN:

4818

European-Finnish (FIN)

AF:

0.795

AC:

8420

AN:

10590

Middle Eastern (MID)

AF:

0.741

AC:

218

AN:

294

European-Non Finnish (NFE)

AF:

0.724

AC:

49223

AN:

67948

Other (OTH)

AF:

0.781

AC:

1651

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1244

2489

3733

4978

6222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

876

1752

2628

3504

4380

<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:

0.736

Hom.:

42856

Bravo

AF:

0.809

TwinsUK

AF:

0.725

AC:

2689

ALSPAC

AF:

0.733

AC:

2825

ESP6500AA

AF:

0.926

AC:

4077

ESP6500EA

AF:

0.730

AC:

6271

ExAC

AF:

0.784

AC:

94737

Asia WGS

AF:

0.892

AC:

3104

AN:

3478

EpiCase

AF:

0.723

EpiControl

AF:

0.723

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.042

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

2.4

(source)

DANN

Benign

0.68

DEOGEN2

Benign

0.0090

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0062

LIST_S2

Benign

0.050

MetaRNN

Benign

9.0e-7

MetaSVM

Benign

-1.1

MutationAssessor

Benign

-0.34

PhyloP100

0.16

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.050

REVEL

Benign

0.032

Sift

Benign

0.29

Sift4G

Benign

0.23

Polyphen

0.0

Vest4

0.0050

MPC

0.25

ClinPred

0.0024

GERP RS

1.4

Varity_R

0.053

gMVP

0.62

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over