Genetic Variant CALHM2:p.Ala96Thr (chr10-103449656-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_015916.5(CALHM2):c.286G>A(p.Ala96Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,613,810 control chromosomes in the GnomAD database, including 468 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 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 ( 41 hom., cov: 32)

Exomes 𝑓: 0.020 ( 427 hom. )

Consequence

CALHM2
NM_015916.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.86

Publications

8 publications found

Variant links:

Genes affected

CALHM2 (HGNC:23493): (calcium homeostasis modulator family member 2) Predicted to enable cation channel activity. Involved in positive regulation of apoptotic process. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

CALHM2 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_015916.5, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0025753677).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0168 (2564/152324) while in subpopulation SAS AF = 0.0201 (97/4830). AF 95% confidence interval is 0.019. There are 41 homozygotes in GnomAd4. There are 1374 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015916.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
CALHM2	NM_015916.5	MANE Select	c.286G>A	p.Ala96Thr	missense	Exon 3 of 4	NP_057000.2
CALHM2	NR_024552.2		n.759G>A		non_coding_transcript_exon	Exon 3 of 4
CALHM2	NR_046344.2		n.759G>A		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CALHM2	ENST00000260743.10	TSL:1 MANE Select	c.286G>A	p.Ala96Thr	missense	Exon 3 of 4	ENSP00000260743.5	Q9HA72-1
CALHM2	ENST00000369788.7	TSL:2	c.286G>A	p.Ala96Thr	missense	Exon 3 of 4	ENSP00000358803.3	Q9HA72-1
CALHM2	ENST00000882006.1		c.286G>A	p.Ala96Thr	missense	Exon 4 of 5	ENSP00000552065.1

Frequencies

GnomAD3 genomes

AF:

0.0169

AC:

2565

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00265

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0147

Gnomad ASJ

AF:

0.0317

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0201

Gnomad FIN

AF:

0.0586

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0199

Gnomad OTH

AF:

0.0172

GnomAD2 exomes

AF:

0.0217

AC:

5462

AN:

251274

AF XY:

0.0225

show subpopulations

Gnomad AFR exome

AF:

0.00283

Gnomad AMR exome

AF:

0.00916

Gnomad ASJ exome

AF:

0.0316

Gnomad EAS exome

AF:

0.000761

Gnomad FIN exome

AF:

0.0641

Gnomad NFE exome

AF:

0.0229

Gnomad OTH exome

AF:

0.0253

GnomAD4 exome

AF:

0.0198

AC:

28995

AN:

1461486

Hom.:

427

Cov.:

AF XY:

0.0201

AC XY:

14609

AN XY:

727062

show subpopulations

African (AFR)

AF:

0.00349

AC:

117

AN:

33480

American (AMR)

AF:

0.00872

AC:

390

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0328

AC:

856

AN:

26136

East Asian (EAS)

AF:

0.000151

AC:

AN:

39700

South Asian (SAS)

AF:

0.0208

AC:

1794

AN:

86258

European-Finnish (FIN)

AF:

0.0626

AC:

3318

AN:

53020

Middle Eastern (MID)

AF:

0.0288

AC:

166

AN:

5768

European-Non Finnish (NFE)

AF:

0.0190

AC:

21155

AN:

1112004

Other (OTH)

AF:

0.0198

AC:

1193

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.481

Heterozygous variant carriers

1947

3894

5841

7788

9735

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

744

1488

2232

2976

3720

<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:

0.0168

AC:

2564

AN:

152324

Hom.:

Cov.:

AF XY:

0.0184

AC XY:

1374

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00265

AC:

110

AN:

41572

American (AMR)

AF:

0.0146

AC:

224

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0317

AC:

110

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0201

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0586

AC:

622

AN:

10608

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0199

AC:

1356

AN:

68032

Other (OTH)

AF:

0.0170

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

125

250

376

501

626

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0187

Hom.:

Bravo

AF:

0.0126

Asia WGS

AF:

0.00779

AC:

AN:

3478

EpiCase

AF:

0.0219

EpiControl

AF:

0.0213

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.67

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.010

Eigen

Benign

-0.13

Eigen_PC

Benign

0.042

FATHMM_MKL

Benign

0.74

LIST_S2

Benign

0.77

MetaRNN

Benign

0.0026

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.7

PhyloP100

2.9

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.82

REVEL

Benign

0.031

Sift

Benign

0.47

Sift4G

Benign

0.61

Varity_R

0.069

gMVP

0.50

Mutation Taster

=92/8

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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