Genetic Variant ARNT2:c.32-11406G>A (chr15-80439474-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

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

The NM_014862.4(ARNT2):c.32-11406G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.233 in 152,034 control chromosomes in the GnomAD database, including 4,899 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 0.23 ( 4899 hom., cov: 33)

Consequence

ARNT2
NM_014862.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.03

Publications

4 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, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
septooptic dysplasia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ARNT2 links:

ENSG00000258010 (HGNC:58450):

ENSG00000258010 links:

Genome browser will be placed here

new If you want to explore the variant's impact on the transcript NM_014862.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

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=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.387 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014862.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARNT2	NM_014862.4	MANE Select	c.32-11406G>A		intron	N/A	NP_055677.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ARNT2	ENST00000303329.9	TSL:1 MANE Select	c.32-11406G>A	intron	N/A	ENSP00000307479.4	Q9HBZ2-1
ARNT2	ENST00000529181.1	TSL:1	n.198-11406G>A	intron	N/A
ARNT2	ENST00000869656.1		c.32-11406G>A	intron	N/A	ENSP00000539715.1

Frequencies

GnomAD3 genomes

AF:

0.233

AC:

35374

AN:

151916

Hom.:

4886

Cov.:

show subpopulations

Gnomad AFR

AF:

0.392

Gnomad AMI

AF:

0.226

Gnomad AMR

AF:

0.157

Gnomad ASJ

AF:

0.171

Gnomad EAS

AF:

0.0875

Gnomad SAS

AF:

0.245

Gnomad FIN

AF:

0.146

Gnomad MID

AF:

0.225

Gnomad NFE

AF:

0.180

Gnomad OTH

AF:

0.226

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

GnomAD4 genome

AF:

0.233

AC:

35424

AN:

152034

Hom.:

4899

Cov.:

AF XY:

0.230

AC XY:

17126

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.392

AC:

16252

AN:

41432

American (AMR)

AF:

0.157

AC:

2403

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.171

AC:

593

AN:

3468

East Asian (EAS)

AF:

0.0875

AC:

453

AN:

5178

South Asian (SAS)

AF:

0.246

AC:

1184

AN:

4818

European-Finnish (FIN)

AF:

0.146

AC:

1546

AN:

10576

Middle Eastern (MID)

AF:

0.218

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.180

AC:

12247

AN:

67972

Other (OTH)

AF:

0.226

AC:

477

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1344

2689

4033

5378

6722

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

366

732

1098

1464

1830

<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:

0.197

Hom.:

10436

Bravo

AF:

0.236

Asia WGS

AF:

0.181

AC:

630

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.031

(source)

DANN

Benign

0.51

PhyloP100

-1.0

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over