Variant chr12-101042440-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

The NM_001286615.2(ANO4):c.1126G>A(p.Val376Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00484 in 1,614,056 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0030 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 15 hom. )

Consequence

ANO4
NM_001286615.2 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.994

Variant links:

Genes affected

ANO4 (HGNC:23837): (anoctamin 4) Enables intracellular calcium activated chloride channel activity. Involved in chloride transport. Located in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ANO4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0071798563).

BP6

Variant 12-101042440-G-A is Benign according to our data. Variant chr12-101042440-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 778657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAdExome4 at 15 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ANO4	NM_001286615.2 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	12/28	ENST00000392977.8	NP_001273544.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ANO4	ENST00000392977.8 linkuse as main transcript	c.1126G>A	p.Val376Ile	missense_variant	12/28	2	NM_001286615.2	ENSP00000376703		Q32M45-1
ANO4	ENST00000644049.1 linkuse as main transcript	c.1624G>A	p.Val542Ile	missense_variant	14/30			ENSP00000494481
ANO4	ENST00000392979.7 linkuse as main transcript	c.1021G>A	p.Val341Ile	missense_variant	11/27	2		ENSP00000376705	P1	Q32M45-2
ANO4	ENST00000548940.1 linkuse as main transcript	n.61G>A		non_coding_transcript_exon_variant	1/4	4

Frequencies

GnomAD3 genomes

AF:

0.00298

AC:

454

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00491

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00463

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00285

AC:

717

AN:

251304

Hom.:

AF XY:

0.00307

AC XY:

417

AN XY:

135810

show subpopulations

Gnomad AFR exome

AF:

0.000800

Gnomad AMR exome

AF:

0.00171

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000523

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.00513

Gnomad OTH exome

AF:

0.00294

GnomAD4 exome

AF:

0.00504

AC:

7366

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00498

AC XY:

3623

AN XY:

727214

show subpopulations

Gnomad4 AFR exome

AF:

0.000597

Gnomad4 AMR exome

AF:

0.00201

Gnomad4 ASJ exome

AF:

0.00268

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000765

Gnomad4 FIN exome

AF:

0.000243

Gnomad4 NFE exome

AF:

0.00618

Gnomad4 OTH exome

AF:

0.00368

GnomAD4 genome

AF:

0.00298

AC:

454

AN:

152228

Hom.:

Cov.:

AF XY:

0.00297

AC XY:

221

AN XY:

74436

show subpopulations

Gnomad4 AFR

AF:

0.00113

Gnomad4 AMR

AF:

0.00491

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00463

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.00441

Hom.:

Bravo

AF:

0.00359

TwinsUK

AF:

0.00809

AC:

ALSPAC

AF:

0.00934

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00535

AC:

ExAC

AF:

0.00306

AC:

371

EpiCase

AF:

0.00371

EpiControl

AF:

0.00445

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 10, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.51

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.041

.;.;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.27

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.63

T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.0072

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.64

.;.;N

MutationTaster

Benign

1.0

D;N;N

PrimateAI

Benign

0.32

PROVEAN

Benign

0.36

.;N;N

REVEL

Benign

0.072

Sift

Benign

0.23

.;T;T

Sift4G

Benign

0.17

.;T;T

Polyphen

0.012, 0.025

.;B;B

Vest4

0.14, 0.12

MVP

0.093

MPC

0.43

ClinPred

0.0037

GERP RS

5.0

Varity_R

0.034

gMVP

0.20

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over