rs2066853

Variant names:

• chr7-17339486-G-A
• rs2066853
• NM_001621.5:c.1661G>A

Variant summary

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

The NM_001621.5(AHR):​c.1661G>A​(p.Arg554Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 1,613,866 control chromosomes in the GnomAD database, including 20,829 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt. Synonymous variant affecting the same amino acid position (i.e. R554R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.22 (5364 hom., cov: 32)
  • Exomes 𝑓: 0.13 (15465 hom.)
• Consequence: AHR NM_001621.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.65

Genes affected

AHR (HGNC:348): (aryl hydrocarbon receptor) The protein encoded by this gene is a ligand-activated helix-loop-helix transcription factor involved in the regulation of biological responses to planar aromatic hydrocarbons. This receptor has been shown to regulate xenobiotic-metabolizing enzymes such as cytochrome P450. Before ligand binding, the encoded protein is sequestered in the cytoplasm; upon ligand binding, this protein moves to the nucleus and stimulates transcription of target genes. [provided by RefSeq, Sep 2015]

ENSG00000283321 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014748573).
• BP6: Variant 7-17339486-G-A is Benign according to our data. Variant chr7-17339486-G-A is described in ClinVar as [Benign]. Clinvar id is 1168239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.447 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AHR	NM_001621.5	c.1661G>A	p.Arg554Lys	missense_variant	Exon 10 of 11	ENST00000242057.9	NP_001612.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AHR	ENST00000242057.9	c.1661G>A	p.Arg554Lys	missense_variant	Exon 10 of 11	1	NM_001621.5	ENSP00000242057.4
ENSG00000283321	ENST00000637807.1	c.1631G>A	p.Arg544Lys	missense_variant	Exon 10 of 12	5		ENSP00000490530.1

Frequencies

GnomAD3 genomes AF: 0.216 AC: 32840 AN: 151982 Hom.: 5335 Cov.: 32

Gnomad AFR AF: 0.452

Gnomad AMI AF: 0.0954

Gnomad AMR AF: 0.155

Gnomad ASJ AF: 0.128

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.115

Gnomad MID AF: 0.184

Gnomad NFE AF: 0.103

Gnomad OTH AF: 0.176

GnomAD2 exomes AF: 0.152 AC: 38185 AN: 250730 AF XY: 0.144

Gnomad AFR exome AF: 0.458

Gnomad AMR exome AF: 0.125

Gnomad ASJ exome AF: 0.122

Gnomad EAS exome AF: 0.354

Gnomad FIN exome AF: 0.111

Gnomad NFE exome AF: 0.100

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.126 AC: 183916 AN: 1461766 Hom.: 15465 Cov.: 33 AF XY: 0.125 AC XY: 90675 AN XY: 727188

Gnomad4 AFR exome AF: 0.460 AC: 15410 AN: 33472

Gnomad4 AMR exome AF: 0.133 AC: 5948 AN: 44714

Gnomad4 ASJ exome AF: 0.124 AC: 3230 AN: 26130

Gnomad4 EAS exome AF: 0.402 AC: 15934 AN: 39682

Gnomad4 SAS exome AF: 0.137 AC: 11853 AN: 86242

Gnomad4 FIN exome AF: 0.112 AC: 5953 AN: 53384

Gnomad4 NFE exome AF: 0.104 AC: 115583 AN: 1111984

Gnomad4 Remaining exome AF: 0.151 AC: 9135 AN: 60390

GnomAD4 genome AF: 0.216 AC: 32915 AN: 152100 Hom.: 5364 Cov.: 32 AF XY: 0.216 AC XY: 16058 AN XY: 74350

Gnomad4 AFR AF: 0.452 AC: 0.452275 AN: 0.452275

Gnomad4 AMR AF: 0.155 AC: 0.154802 AN: 0.154802

Gnomad4 ASJ AF: 0.128 AC: 0.12788 AN: 0.12788

Gnomad4 EAS AF: 0.377 AC: 0.377271 AN: 0.377271

Gnomad4 SAS AF: 0.145 AC: 0.144546 AN: 0.144546

Gnomad4 FIN AF: 0.115 AC: 0.115435 AN: 0.115435

Gnomad4 NFE AF: 0.103 AC: 0.102624 AN: 0.102624

Gnomad4 OTH AF: 0.175 AC: 0.174551 AN: 0.174551

Alfa AF: 0.141 Hom.: 9049

Bravo AF: 0.231

TwinsUK AF: 0.105 AC: 389

ALSPAC AF: 0.116 AC: 447

ESP6500AA AF: 0.444 AC: 1957

ESP6500EA AF: 0.101 AC: 870

ExAC AF: 0.157 AC: 18996

Asia WGS AF: 0.237 AC: 822 AN: 3478

EpiCase AF: 0.103

EpiControl AF: 0.0986

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 22, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 29185192, 10739168, 21454829, 21742528, 18818557) -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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	-0.81	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.8
DANN	Benign	0.55
DEOGEN2	Benign	0.079	.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.025	N
LIST_S2	Benign	0.41	T;.;T
MetaRNN	Benign	0.0015	T;T;T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	-1.5	.;N;.
PrimateAI	Benign	0.27	T
PROVEAN	Benign	1.2	.;N;.
REVEL	Benign	0.040
Sift	Benign	1.0	.;T;.
Sift4G	Benign	1.0	.;T;.
Polyphen		0.0	.;B;.
Vest4		0.0050
MPC		0.11
ClinPred		0.0014	T
GERP RS		0.60
Varity_R		0.035
gMVP		0.13
Mutation Taster		=99/1	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

Publications

LitVar

Other links and lift over

dbSNP: rs2066853; hg19: chr7-17379110; COSMIC: COSV54123264; COSMIC: COSV54123264;