12-45429252-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001025356.3(ANO6):c.2674G>C(p.Val892Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00329 in 1,613,900 control chromosomes in the GnomAD database, including 155 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.018 ( 80 hom., cov: 32)

Exomes 𝑓: 0.0017 ( 75 hom. )

Consequence

ANO6
NM_001025356.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.469

Publications

7 publications found

Variant links:

Genes affected

ANO6 (HGNC:25240): (anoctamin 6) This gene encodes a multi-pass transmembrane protein that belongs to the anoctamin family. This protein is an essential component for the calcium-dependent exposure of phosphatidylserine on the cell surface. The scrambling of phospholipid occurs in various biological systems, such as when blood platelets are activated, they expose phosphatidylserine to trigger the clotting system. Mutations in this gene are associated with Scott syndrome. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2011]

ANO6 Gene-Disease associations (from GenCC):

Scott syndrome
Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, ClinGen, Labcorp Genetics (formerly Invitae)

ANO6 links:

ENSG00000293678 (HGNC:):

ENSG00000293678 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001354903).

BP6

Variant 12-45429252-G-C is Benign according to our data. Variant chr12-45429252-G-C is described in ClinVar as Benign. ClinVar VariationId is 257145.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0604 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001025356.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANO6	NM_001025356.3	MANE Select	c.2674G>C	p.Val892Leu	missense	Exon 20 of 20	NP_001020527.2
ANO6	NM_001204803.2		c.2737G>C	p.Val913Leu	missense	Exon 21 of 21	NP_001191732.1
ANO6	NM_001410973.1		c.2641G>C	p.Val881Leu	missense	Exon 20 of 20	NP_001397902.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ANO6	ENST00000320560.13	TSL:1 MANE Select	c.2674G>C	p.Val892Leu	missense	Exon 20 of 20	ENSP00000320087.8
ANO6	ENST00000423947.7	TSL:1	c.2737G>C	p.Val913Leu	missense	Exon 21 of 21	ENSP00000409126.3
ANO6	ENST00000441606.2	TSL:1	c.2620G>C	p.Val874Leu	missense	Exon 20 of 20	ENSP00000413137.2

Frequencies

GnomAD3 genomes

AF:

0.0181

AC:

2747

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0625

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00805

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:

0.000103

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00495

AC:

1240

AN:

250602

AF XY:

0.00319

show subpopulations

Gnomad AFR exome

AF:

0.0691

Gnomad AMR exome

AF:

0.00284

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000795

Gnomad OTH exome

AF:

0.00147

GnomAD4 exome

AF:

0.00175

AC:

2556

AN:

1461596

Hom.:

Cov.:

AF XY:

0.00137

AC XY:

995

AN XY:

727098

show subpopulations

African (AFR)

AF:

0.0639

AC:

2140

AN:

33468

American (AMR)

AF:

0.00342

AC:

153

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39640

South Asian (SAS)

AF:

0.000104

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53362

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.0000297

AC:

AN:

1111894

Other (OTH)

AF:

0.00346

AC:

209

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

143

287

430

574

717

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.0181

AC:

2751

AN:

152304

Hom.:

Cov.:

AF XY:

0.0174

AC XY:

1295

AN XY:

74472

show subpopulations

African (AFR)

AF:

0.0624

AC:

2594

AN:

41546

American (AMR)

AF:

0.00804

AC:

123

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5196

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000103

AC:

AN:

68028

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

132

264

396

528

660

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

150

<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:

0.00124

Hom.:

Bravo

AF:

0.0215

ESP6500AA

AF:

0.0708

AC:

312

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00641

AC:

778

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

Jan 26, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.59

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.1

(source)

DANN

Benign

0.88

DEOGEN2

Benign

0.031

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.047

LIST_S2

Benign

0.74

MetaRNN

Benign

0.0014

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PhyloP100

0.47

PrimateAI

Benign

0.30

PROVEAN

Benign

0.080

REVEL

Benign

0.057

Sift

Benign

0.32

Sift4G

Benign

0.74

Polyphen

0.0010

Vest4

0.035

MutPred

0.27

Loss of catalytic residue at V892 (P = 0.0987)

MVP

0.44

MPC

0.18

ClinPred

0.00082

GERP RS

-2.1

Varity_R

0.024

gMVP

0.23

Mutation Taster

=99/1

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

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over