rs2292596

Variant names:

• chr5-422840-C-G
• rs2292596
• NM_001377236.1:c.553C>G

Your query was ambiguous. Multiple possible variants found:

• chr5-422840-C-G
• chr5-422840-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001377236.1(AHRR):​c.553C>G​(p.Pro185Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.375 in 1,612,388 control chromosomes in the GnomAD database, including 117,292 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.32 (8656 hom., cov: 32)
  • Exomes 𝑓: 0.38 (108636 hom.)
• Consequence: AHRR NM_001377236.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.914
• Publications: 64 publications found

Genes affected

AHRR (HGNC:346): (aryl hydrocarbon receptor repressor) The protein encoded by this gene participates in the aryl hydrocarbon receptor (AhR) signaling cascade, which mediates dioxin toxicity, and is involved in regulation of cell growth and differentiation. It functions as a feedback modulator by repressing AhR-dependent gene expression. Alternatively spliced transcript variants encoding different isoforms have been described for this gene. [provided by RefSeq, Jun 2011]

PDCD6-AHRR (HGNC:54724): (PDCD6-AHRR readthrough (NMD candidate)) Predicted to enable calcium ion binding activity. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045746267).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.424 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001377236.1. 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
	AHRR	NM_001377236.1	MANE Select	c.553C>G	p.Pro185Ala	missense	Exon 6 of 11	NP_001364165.1	A0A7I2PK40
	AHRR	NM_001377239.1		c.553C>G	p.Pro185Ala	missense	Exon 6 of 11	NP_001364168.1	A0A7I2PK40
	PDCD6-AHRR	NR_165159.2		n.846C>G		non_coding_transcript_exon	Exon 8 of 14

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AHRR	ENST00000684583.1	MANE Select	c.553C>G	p.Pro185Ala	missense	Exon 6 of 11	ENSP00000507476.1	A0A7I2PK40
	AHRR	ENST00000316418.10	TSL:1	c.553C>G	p.Pro185Ala	missense	Exon 6 of 11	ENSP00000323816.6	A0A7I2PK40
	PDCD6-AHRR	ENST00000505113.6	TSL:1	n.*549C>G		non_coding_transcript_exon	Exon 8 of 13	ENSP00000424601.2	A0A6Q8PH81

Frequencies

GnomAD3 genomes AF: 0.318 AC: 48390 AN: 151996 Hom.: 8660 Cov.: 32

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.283

Gnomad ASJ AF: 0.426

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.439

Gnomad FIN AF: 0.457

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.389

Gnomad OTH AF: 0.322

GnomAD2 exomes AF: 0.375 AC: 93047 AN: 248018 AF XY: 0.387

Gnomad AFR exome AF: 0.143

Gnomad AMR exome AF: 0.254

Gnomad ASJ exome AF: 0.430

Gnomad EAS exome AF: 0.395

Gnomad FIN exome AF: 0.455

Gnomad NFE exome AF: 0.399

Gnomad OTH exome AF: 0.397

GnomAD4 exome AF: 0.381 AC: 556402 AN: 1460274 Hom.: 108636 Cov.: 46 AF XY: 0.385 AC XY: 279507 AN XY: 726198

African (AFR) AF: 0.141 AC: 4714 AN: 33452

American (AMR) AF: 0.262 AC: 11669 AN: 44578

Ashkenazi Jewish (ASJ) AF: 0.436 AC: 11361 AN: 26072

East Asian (EAS) AF: 0.390 AC: 15441 AN: 39636

South Asian (SAS) AF: 0.447 AC: 38515 AN: 86130

European-Finnish (FIN) AF: 0.449 AC: 23903 AN: 53292

Middle Eastern (MID) AF: 0.445 AC: 2562 AN: 5756

European-Non Finnish (NFE) AF: 0.383 AC: 425868 AN: 1111042

Other (OTH) AF: 0.371 AC: 22369 AN: 60316

GnomAD4 genome AF: 0.318 AC: 48383 AN: 152114 Hom.: 8656 Cov.: 32 AF XY: 0.325 AC XY: 24178 AN XY: 74362

African (AFR) AF: 0.147 AC: 6094 AN: 41512

American (AMR) AF: 0.283 AC: 4325 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.426 AC: 1479 AN: 3472

East Asian (EAS) AF: 0.387 AC: 2001 AN: 5168

South Asian (SAS) AF: 0.439 AC: 2115 AN: 4814

European-Finnish (FIN) AF: 0.457 AC: 4834 AN: 10580

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.389 AC: 26463 AN: 67964

Other (OTH) AF: 0.321 AC: 678 AN: 2112

Alfa AF: 0.349 Hom.: 3107

Bravo AF: 0.298

TwinsUK AF: 0.374 AC: 1386

ALSPAC AF: 0.366 AC: 1409

ESP6500AA AF: 0.147 AC: 593

ESP6500EA AF: 0.378 AC: 3154

ExAC AF: 0.377 AC: 45620

Asia WGS AF: 0.416 AC: 1446 AN: 3478

EpiCase AF: 0.391

EpiControl AF: 0.389

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.58
DEOGEN2	Benign	0.088	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.48
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.51	T
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.2	M
PhyloP100		0.91
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.075
Sift	Benign	0.072	T
Sift4G	Benign	0.41	T
Polyphen		0.067	B
Vest4		0.17
MPC		0.63
ClinPred		0.028	T
GERP RS		3.1
Varity_R		0.044
gMVP		0.22
Mutation Taster		=95/5	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: rs2292596; hg19: chr5-422955; COSMIC: COSV57082396; COSMIC: COSV57082396;