15-80451009-C-T

Variant names:

• chr15-80451009-C-T
• rs2278708
• NM_014862.4:c.146+15C>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.146+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0422 in 1,608,010 control chromosomes in the GnomAD database, including 2,075 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (154 hom., cov: 33)
  • Exomes 𝑓: 0.043 (1921 hom.)
• Consequence: ARNT2 NM_014862.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.71
• Publications: 7 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: G2P, Labcorp Genetics (formerly Invitae)
• 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 (BayesDel_noAF=-0.9).
• BP6: Variant 15-80451009-C-T is Benign according to our data. Variant chr15-80451009-C-T is described in ClinVar as Benign. ClinVar VariationId is 1165309.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.154 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.146+15C>T		intron	N/A	NP_055677.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ARNT2	ENST00000303329.9	TSL:1 MANE Select	c.146+15C>T		intron	N/A	ENSP00000307479.4	Q9HBZ2-1
	ARNT2	ENST00000529181.1	TSL:1	n.312+15C>T		intron	N/A
	ARNT2	ENST00000869656.1		c.146+15C>T		intron	N/A	ENSP00000539715.1

Frequencies

GnomAD3 genomes AF: 0.0346 AC: 5266 AN: 152222 Hom.: 155 Cov.: 33

Gnomad AFR AF: 0.00774

Gnomad AMI AF: 0.0164

Gnomad AMR AF: 0.0405

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.164

Gnomad SAS AF: 0.0826

Gnomad FIN AF: 0.0124

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0401

GnomAD2 exomes AF: 0.0517 AC: 12875 AN: 249066 AF XY: 0.0515

Gnomad AFR exome AF: 0.00632

Gnomad AMR exome AF: 0.0531

Gnomad ASJ exome AF: 0.0715

Gnomad EAS exome AF: 0.170

Gnomad FIN exome AF: 0.0138

Gnomad NFE exome AF: 0.0395

Gnomad OTH exome AF: 0.0505

GnomAD4 exome AF: 0.0430 AC: 62629 AN: 1455670 Hom.: 1921 Cov.: 30 AF XY: 0.0436 AC XY: 31593 AN XY: 724178

African (AFR) AF: 0.00627 AC: 209 AN: 33314

American (AMR) AF: 0.0523 AC: 2324 AN: 44456

Ashkenazi Jewish (ASJ) AF: 0.0751 AC: 1961 AN: 26098

East Asian (EAS) AF: 0.172 AC: 6830 AN: 39600

South Asian (SAS) AF: 0.0661 AC: 5695 AN: 86130

European-Finnish (FIN) AF: 0.0155 AC: 812 AN: 52334

Middle Eastern (MID) AF: 0.0325 AC: 187 AN: 5754

European-Non Finnish (NFE) AF: 0.0376 AC: 41630 AN: 1107824

Other (OTH) AF: 0.0496 AC: 2981 AN: 60160

GnomAD4 genome AF: 0.0346 AC: 5264 AN: 152340 Hom.: 154 Cov.: 33 AF XY: 0.0348 AC XY: 2592 AN XY: 74486

African (AFR) AF: 0.00769 AC: 320 AN: 41590

American (AMR) AF: 0.0405 AC: 620 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3470

East Asian (EAS) AF: 0.163 AC: 847 AN: 5192

South Asian (SAS) AF: 0.0831 AC: 401 AN: 4826

European-Finnish (FIN) AF: 0.0124 AC: 132 AN: 10612

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0381 AC: 2590 AN: 68024

Other (OTH) AF: 0.0392 AC: 83 AN: 2116

Alfa AF: 0.0424 Hom.: 203

Bravo AF: 0.0371

Asia WGS AF: 0.115 AC: 398 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.14
DANN	Benign	0.78
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2278708; hg19: chr15-80743350; COSMIC: COSV57585611;