Genetic Variant NM_014862.4:c.31+22499T>C (chr15-80427045-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_014862.4(ARNT2):c.31+22499T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.31 in 152,088 control chromosomes in the GnomAD database, including 7,507 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.31 ( 7507 hom., cov: 32)

Consequence

ARNT2
NM_014862.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.482

Publications

2 publications found

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 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

ARNT2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.95).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.519 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ARNT2	NM_014862.4 link	c.31+22499T>C		intron_variant	Intron 1 of 18	ENST00000303329.9	NP_055677.3	Q9HBZ2-1X5DQN9Q7Z3A3Q86TN1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ARNT2	ENST00000303329.9 link	c.31+22499T>C		intron_variant	Intron 1 of 18	1	NM_014862.4	ENSP00000307479.4		Q9HBZ2-1
ARNT2	ENST00000529181.1 link	n.197+22499T>C		intron_variant	Intron 1 of 4	1

Frequencies

GnomAD3 genomes

AF:

0.310

AC:

47039

AN:

151970

Hom.:

7501

Cov.:

show subpopulations

Gnomad AFR

AF:

0.352

Gnomad AMI

AF:

0.285

Gnomad AMR

AF:

0.376

Gnomad ASJ

AF:

0.289

Gnomad EAS

AF:

0.536

Gnomad SAS

AF:

0.359

Gnomad FIN

AF:

0.241

Gnomad MID

AF:

0.323

Gnomad NFE

AF:

0.260

Gnomad OTH

AF:

0.310

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.310

AC:

47077

AN:

152088

Hom.:

7507

Cov.:

AF XY:

0.311

AC XY:

23119

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.352

AC:

14598

AN:

41472

American (AMR)

AF:

0.376

AC:

5739

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.289

AC:

1003

AN:

3470

East Asian (EAS)

AF:

0.536

AC:

2768

AN:

5164

South Asian (SAS)

AF:

0.360

AC:

1729

AN:

4808

European-Finnish (FIN)

AF:

0.241

AC:

2548

AN:

10586

Middle Eastern (MID)

AF:

0.320

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.260

AC:

17690

AN:

67996

Other (OTH)

AF:

0.308

AC:

649

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

1643

3286

4929

6572

8215

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

468

936

1404

1872

2340

<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:

0.282

Hom.:

9391

Bravo

AF:

0.327

Asia WGS

AF:

0.428

AC:

1486

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.95

CADD

Benign

0.35

(source)

DANN

Benign

0.51

PhyloP100

-0.48

Mutation Taster

=100/0

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over