rs4072568

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_014862.4(ARNT2):c.2035G>A(p.Gly679Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.18 in 1,613,874 control chromosomes in the GnomAD database, including 28,030 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G679C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.16 ( 2034 hom., cov: 32)

Exomes 𝑓: 0.18 ( 25996 hom. )

Consequence

ARNT2
NM_014862.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 2.82

Variant links:

Genes affected

ARNT2 (HGNC:16876): (aryl hydrocarbon receptor nuclear translocator 2) This gene encodes a member of the basic-helix-loop-helix-Per-Arnt-Sim (bHLH-PAS) superfamily of transcription factors. The encoded protein acts as a partner for several sensor proteins of the bHLH-PAS family, forming heterodimers with the sensor proteins that bind regulatory DNA sequences in genes responsive to developmental and environmental stimuli. Under hypoxic conditions, the encoded protein complexes with hypoxia-inducible factor 1alpha in the nucleus and this complex binds to hypoxia-responsive elements in enhancers and promoters of oxygen-responsive genes. A highly similar protein in mouse forms functional complexes with both aryl hydrocarbon receptors and Single-minded proteins, suggesting additional roles for the encoded protein in the metabolism of xenobiotic compounds and the regulation of neurogenesis, respectively. [provided by RefSeq, Dec 2013]

ARNT2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012139976).

BP6

Variant 15-80591684-G-A is Benign according to our data. Variant chr15-80591684-G-A is described in ClinVar as [Benign]. Clinvar id is 1165402.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ARNT2	NM_014862.4 linkuse as main transcript	c.2035G>A	p.Gly679Ser	missense_variant	18/19	ENST00000303329.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ARNT2	ENST00000303329.9 linkuse as main transcript	c.2035G>A	p.Gly679Ser	missense_variant	18/19	1	NM_014862.4	P1	Q9HBZ2-1
ARNT2	ENST00000527771.5 linkuse as main transcript	c.2002G>A	p.Gly668Ser	missense_variant	18/19	2			Q9HBZ2-2
ARNT2	ENST00000533983.5 linkuse as main transcript	c.2002G>A	p.Gly668Ser	missense_variant	19/20	5			Q9HBZ2-2

Frequencies

GnomAD3 genomes

AF:

0.157

AC:

23910

AN:

152014

Hom.:

2036

Cov.:

show subpopulations

Gnomad AFR

AF:

0.132

Gnomad AMI

AF:

0.286

Gnomad AMR

AF:

0.146

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.00290

Gnomad SAS

AF:

0.163

Gnomad FIN

AF:

0.126

Gnomad MID

AF:

0.180

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.154

GnomAD3 exomes

AF:

0.153

AC:

38314

AN:

251236

Hom.:

3485

AF XY:

0.158

AC XY:

21470

AN XY:

135786

show subpopulations

Gnomad AFR exome

AF:

0.135

Gnomad AMR exome

AF:

0.105

Gnomad ASJ exome

AF:

0.181

Gnomad EAS exome

AF:

0.00266

Gnomad SAS exome

AF:

0.175

Gnomad FIN exome

AF:

0.118

Gnomad NFE exome

AF:

0.191

Gnomad OTH exome

AF:

0.161

GnomAD4 exome

AF:

0.182

AC:

266609

AN:

1461742

Hom.:

25996

Cov.:

AF XY:

0.183

AC XY:

133210

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.129

Gnomad4 AMR exome

AF:

0.110

Gnomad4 ASJ exome

AF:

0.181

Gnomad4 EAS exome

AF:

0.00151

Gnomad4 SAS exome

AF:

0.181

Gnomad4 FIN exome

AF:

0.125

Gnomad4 NFE exome

AF:

0.197

Gnomad4 OTH exome

AF:

0.171

GnomAD4 genome

AF:

0.157

AC:

23924

AN:

152132

Hom.:

2034

Cov.:

AF XY:

0.154

AC XY:

11476

AN XY:

74378

show subpopulations

Gnomad4 AFR

AF:

0.131

Gnomad4 AMR

AF:

0.146

Gnomad4 ASJ

AF:

0.171

Gnomad4 EAS

AF:

0.00290

Gnomad4 SAS

AF:

0.163

Gnomad4 FIN

AF:

0.126

Gnomad4 NFE

AF:

0.189

Gnomad4 OTH

AF:

0.152

Alfa

AF:

0.183

Hom.:

4523

Bravo

AF:

0.156

TwinsUK

AF:

0.198

AC:

735

ALSPAC

AF:

0.196

AC:

755

ESP6500AA

AF:

0.137

AC:

602

ESP6500EA

AF:

0.196

AC:

1684

ExAC

AF:

0.156

AC:

18973

Asia WGS

AF:

0.0730

AC:

253

AN:

3478

EpiCase

AF:

0.189

EpiControl

AF:

0.192

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

ARNT2-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 01, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Webb-Dattani syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 14, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.057

BayesDel_addAF

Benign

-0.74

BayesDel_noAF

Benign

-0.70

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.19

T;.;.;.

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.43

FATHMM_MKL

Benign

0.42

LIST_S2

Uncertain

0.91

D;D;.;D

MetaRNN

Benign

0.0012

T;T;T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-1.6

N;.;.;.

MutationTaster

Benign

0.79

P;P;P

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

N;.;N;N

REVEL

Benign

0.12

Sift

Benign

0.97

T;.;T;T

Sift4G

Benign

0.63

T;T;T;T

Polyphen

0.0010

B;.;.;.

Vest4

0.027

MPC

0.29

ClinPred

0.014

GERP RS

1.7

Varity_R

0.073

gMVP

0.15

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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