rs4072568

Variant names:

• chr15-80591684-G-A
• rs4072568
• NM_014862.4:c.2035G>A

Your query was ambiguous. Multiple possible variants found:

• chr15-80591684-G-A
• chr15-80591684-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.82
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• Webb-Dattani syndrome

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P
• septooptic dysplasia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ARNT2	NM_014862.4	c.2035G>A	p.Gly679Ser	missense_variant	Exon 18 of 19	ENST00000303329.9	NP_055677.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARNT2	ENST00000303329.9	c.2035G>A	p.Gly679Ser	missense_variant	Exon 18 of 19	1	NM_014862.4	ENSP00000307479.4
ARNT2	ENST00000527771.5	c.2002G>A	p.Gly668Ser	missense_variant	Exon 18 of 19	2		ENSP00000453792.1
ARNT2	ENST00000533983.5	c.2002G>A	p.Gly668Ser	missense_variant	Exon 19 of 20	5		ENSP00000453651.1

Frequencies

GnomAD3 genomes AF: 0.157 AC: 23910 AN: 152014 Hom.: 2036 Cov.: 32

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

GnomAD2 exomes AF: 0.153 AC: 38314 AN: 251236 AF XY: 0.158

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 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.: 33 AF XY: 0.183 AC XY: 133210 AN XY: 727182

African (AFR) AF: 0.129 AC: 4312 AN: 33472

American (AMR) AF: 0.110 AC: 4924 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.181 AC: 4742 AN: 26130

East Asian (EAS) AF: 0.00151 AC: 60 AN: 39700

South Asian (SAS) AF: 0.181 AC: 15593 AN: 86254

European-Finnish (FIN) AF: 0.125 AC: 6700 AN: 53420

Middle Eastern (MID) AF: 0.184 AC: 1059 AN: 5764

European-Non Finnish (NFE) AF: 0.197 AC: 218873 AN: 1111904

Other (OTH) AF: 0.171 AC: 10346 AN: 60384

GnomAD4 genome AF: 0.157 AC: 23924 AN: 152132 Hom.: 2034 Cov.: 32 AF XY: 0.154 AC XY: 11476 AN XY: 74378

African (AFR) AF: 0.131 AC: 5459 AN: 41516

American (AMR) AF: 0.146 AC: 2237 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.171 AC: 595 AN: 3472

East Asian (EAS) AF: 0.00290 AC: 15 AN: 5166

South Asian (SAS) AF: 0.163 AC: 784 AN: 4814

European-Finnish (FIN) AF: 0.126 AC: 1336 AN: 10600

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12865 AN: 67968

Other (OTH) AF: 0.152 AC: 321 AN: 2108

Alfa AF: 0.178 Hom.: 5860

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

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

ARNT2-related disorder Benign:1

Nov 01, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.057
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.19	T;.;.;.
Eigen	Benign	-0.65
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.42	N
LIST_S2	Uncertain	0.91	D;D;.;D
MetaRNN	Benign	0.0012	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-1.6	N;.;.;.
PhyloP100		2.8
PrimateAI	Benign	0.46	T
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	T
GERP RS		1.7
Varity_R		0.073
gMVP		0.15
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4072568; hg19: chr15-80884025; COSMIC: COSV57582094;