10-4995382-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The NM_001393392.1(AKR1C2):c.783G>A(p.Leu261=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0027 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0015 (2 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKR1C2 NM_001393392.1 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.14

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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 10-4995382-C-T is Benign according to our data. Variant chr10-4995382-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3056884.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-4995382-C-T is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.14 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C2	NM_001393392.1	c.783G>A	p.Leu261=	synonymous_variant	7/9	ENST00000380753.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C2	ENST00000380753.9	c.783G>A	p.Leu261=	synonymous_variant	7/9	1	NM_001393392.1	P1
AKR1C2	ENST00000421196.7	c.705G>A	p.Leu235=	synonymous_variant	6/8	1
AKR1C2	ENST00000460124.5	n.2243G>A		non_coding_transcript_exon_variant	6/8	5

Frequencies

GnomAD3 genomes AF: 0.00 AC: 383 AN: 143512 Hom.: 0 Cov.: 20 FAILED QC

Gnomad AFR AF: 0.00180

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.0103

Gnomad EAS AF: 0.000202

Gnomad SAS AF: 0.00370

Gnomad FIN AF: 0.00107

Gnomad MID AF: 0.00329

Gnomad NFE AF: 0.00322

Gnomad OTH AF: 0.00365

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00148 AC: 2056 AN: 1391382 Hom.: 2 Cov.: 31 AF XY: 0.00188 AC XY: 1294 AN XY: 689558

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00242

Gnomad4 ASJ exome AF: 0.00599

Gnomad4 EAS exome AF: 0.000485

Gnomad4 SAS exome AF: 0.00359

Gnomad4 FIN exome AF: 0.000948

Gnomad4 NFE exome AF: 0.00123

Gnomad4 OTH exome AF: 0.00182

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00267 AC: 383 AN: 143618 Hom.: 0 Cov.: 20 AF XY: 0.00253 AC XY: 177 AN XY: 69986

Gnomad4 AFR AF: 0.00179

Gnomad4 AMR AF: 0.00267

Gnomad4 ASJ AF: 0.0103

Gnomad4 EAS AF: 0.000202

Gnomad4 SAS AF: 0.00370

Gnomad4 FIN AF: 0.00107

Gnomad4 NFE AF: 0.00322

Gnomad4 OTH AF: 0.00362

Alfa AF: 0.00664 Hom.: 0

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AKR1C2-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 03, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	5.7
Dann	Benign	0.92

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: rs781828411; hg19: chr10-5037574; COSMIC: COSV66332558; COSMIC: COSV66332558;