rs2854482

Positions:

• chr10-5001629-A-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001393392.1(AKR1C2):​c.137T>A​(p.Phe46Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,613,932 control chromosomes in the GnomAD database, including 1,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.065 (548 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1264 hom.)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35

Genes affected

AKR1C2 (HGNC:385): (aldo-keto reductase family 1 member C2) This gene encodes a member of the aldo/keto reductase superfamily, which consists of more than 40 known enzymes and proteins. These enzymes catalyze the conversion of aldehydes and ketones to their corresponding alcohols using NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme binds bile acid with high affinity, and shows minimal 3-alpha-hydroxysteroid dehydrogenase activity. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. Three transcript variants encoding two different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024238825).
• BP6: Variant 10-5001629-A-T is Benign according to our data. Variant chr10-5001629-A-T is described in ClinVar as [Benign]. Clinvar id is 1297289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.137T>A	p.Phe46Tyr	missense_variant	2/9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.137T>A	p.Phe46Tyr	missense_variant	2/9	1	NM_001393392.1	ENSP00000370129	P1

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9893 AN: 152144 Hom.: 550 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0483

GnomAD3 exomes AF: 0.0371 AC: 9331 AN: 251392 Hom.: 309 AF XY: 0.0357 AC XY: 4844 AN XY: 135868

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0561

Gnomad EAS exome AF: 0.00816

Gnomad SAS exome AF: 0.0279

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0351 AC: 51320 AN: 1461670 Hom.: 1264 Cov.: 31 AF XY: 0.0350 AC XY: 25431 AN XY: 727140

Gnomad4 AFR exome AF: 0.160

Gnomad4 AMR exome AF: 0.0204

Gnomad4 ASJ exome AF: 0.0563

Gnomad4 EAS exome AF: 0.00466

Gnomad4 SAS exome AF: 0.0279

Gnomad4 FIN exome AF: 0.0236

Gnomad4 NFE exome AF: 0.0334

Gnomad4 OTH exome AF: 0.0379

GnomAD4 genome AF: 0.0651 AC: 9910 AN: 152262 Hom.: 548 Cov.: 33 AF XY: 0.0622 AC XY: 4632 AN XY: 74460

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0346

Gnomad4 ASJ AF: 0.0637

Gnomad4 EAS AF: 0.00907

Gnomad4 SAS AF: 0.0232

Gnomad4 FIN AF: 0.0252

Gnomad4 NFE AF: 0.0346

Gnomad4 OTH AF: 0.0483

Alfa AF: 0.0394 Hom.: 114

Bravo AF: 0.0689

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.138 AC: 610

ESP6500EA AF: 0.0349 AC: 300

ExAC AF: 0.0397 AC: 4820

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0353

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 09, 2018	This variant is associated with the following publications: (PMID: 21217827, 19258517) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.52
DEOGEN2	Benign	0.058	T;.;.;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.69	T;D;T;D
MetaRNN	Benign	0.0024	T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.3	N;.;.;N
MutationTaster	Benign	0.96	P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N;N;.;N
REVEL	Benign	0.061
Sift	Benign	1.0	T;T;.;T
Sift4G	Benign	1.0	T;T;.;T
Polyphen		0.038	B;B;.;.
Vest4		0.18
MPC		0.60
ClinPred		0.017	T
GERP RS		1.1
Varity_R		0.56
gMVP		0.62

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: rs2854482; hg19: chr10-5043821;