Genetic Variant NM_001364791.2:c.266G>A (chr12-5921308-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_001364791.2(ANO2):c.266G>A(p.Arg89His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000667 in 1,613,916 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0025 ( 5 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 2 hom. )

Consequence

ANO2
NM_001364791.2 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.21

Publications

5 publications found

Variant links:

Genes affected

ANO2 (HGNC:1183): (anoctamin 2) ANO2 belongs to a family of calcium-activated chloride channels (CaCCs) (reviewed by Hartzell et al., 2009 [PubMed 19015192]).[supplied by OMIM, Jan 2011]

ANO2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0059717596).

BP6

Variant 12-5921308-C-T is Benign according to our data. Variant chr12-5921308-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2642600.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001364791.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO2	NM_001364791.2	MANE Select	c.266G>A	p.Arg89His	missense	Exon 3 of 25	NP_001351720.1	A0A804HIY3
ANO2	NM_001278596.3		c.266G>A	p.Arg89His	missense	Exon 3 of 27	NP_001265525.1	Q9NQ90-1
ANO2	NM_001278597.3		c.254G>A	p.Arg85His	missense	Exon 3 of 27	NP_001265526.1	Q9NQ90-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ANO2	ENST00000682330.1	MANE Select	c.266G>A	p.Arg89His	missense	Exon 3 of 25	ENSP00000507275.1	A0A804HIY3
ANO2	ENST00000650848.1		c.266G>A	p.Arg89His	missense	Exon 3 of 27	ENSP00000498903.1	Q9NQ90-1
ANO2	ENST00000356134.9	TSL:5	c.254G>A	p.Arg85His	missense	Exon 3 of 27	ENSP00000348453.5	Q9NQ90-2

Frequencies

GnomAD3 genomes

AF:

0.00254

AC:

386

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00775

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00950

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.000967

AC:

241

AN:

249184

AF XY:

0.000806

show subpopulations

Gnomad AFR exome

AF:

0.00853

Gnomad AMR exome

AF:

0.000261

Gnomad ASJ exome

AF:

0.00746

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000159

Gnomad OTH exome

AF:

0.000827

GnomAD4 exome

AF:

0.000471

AC:

689

AN:

1461694

Hom.:

Cov.:

AF XY:

0.000424

AC XY:

308

AN XY:

727132

show subpopulations

African (AFR)

AF:

0.00780

AC:

261

AN:

33480

American (AMR)

AF:

0.000380

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00869

AC:

227

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000232

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53398

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000980

AC:

109

AN:

1111866

Other (OTH)

AF:

0.00114

AC:

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

128

171

214

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00254

AC:

387

AN:

152222

Hom.:

Cov.:

AF XY:

0.00258

AC XY:

192

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00775

AC:

322

AN:

41524

American (AMR)

AF:

0.000980

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00950

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10608

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000191

AC:

AN:

68016

Other (OTH)

AF:

0.00189

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00132

Hom.:

Bravo

AF:

0.00274

ESP6500AA

AF:

0.00719

AC:

ESP6500EA

AF:

0.000474

AC:

ExAC

AF:

0.000892

AC:

108

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000178

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.096

Eigen

Benign

-0.036

Eigen_PC

Benign

-0.042

FATHMM_MKL

Uncertain

0.80

LIST_S2

Benign

0.73

M_CAP

Benign

0.070

MetaRNN

Benign

0.0060

MetaSVM

Benign

-0.61

PhyloP100

1.2

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.33

REVEL

Benign

0.17

Sift

Benign

0.23

Sift4G

Benign

0.15

Vest4

0.18

MVP

0.29

MPC

0.080

ClinPred

0.014

GERP RS

4.2

gMVP

0.24

Mutation Taster

=100/0

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over