Variant 10-4995339-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001393392.1(AKR1C2):c.826C>T(p.Arg276Cys) variant causes a missense 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000041 ( 0 hom., cov: 20)

Exomes 𝑓: 0.000046 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

AKR1C2
NM_001393392.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.464

Variant links:

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]

AKR1C2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01775527).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1C2	NM_001393392.1 linkuse as main transcript	c.826C>T	p.Arg276Cys	missense_variant	7/9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9 linkuse as main transcript	c.826C>T	p.Arg276Cys	missense_variant	7/9	1	NM_001393392.1	ENSP00000370129	P1	P52895-1
AKR1C2	ENST00000421196.7 linkuse as main transcript	c.748C>T	p.Arg250Cys	missense_variant	6/8	1		ENSP00000392694
AKR1C2	ENST00000460124.5 linkuse as main transcript	n.2286C>T		non_coding_transcript_exon_variant	6/8	5

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

147074

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.0000252

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00103

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000119

AC:

AN:

75608

Hom.:

AF XY:

0.0000796

AC XY:

AN XY:

37684

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000851

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000696

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000736

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000462

AC:

AN:

1364946

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

669062

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000926

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000273

Gnomad4 SAS exome

AF:

0.0000824

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.0000406

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.0000408

AC:

AN:

147074

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

71394

show subpopulations

Gnomad4 AFR

AF:

0.0000252

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00103

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000375

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 25, 2023

The c.826C>T (p.R276C) alteration is located in exon 9 (coding exon 7) of the AKR1C2 gene. This alteration results from a C to T substitution at nucleotide position 826, causing the arginine (R) at amino acid position 276 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.67

FATHMM_MKL

Benign

0.036

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Benign

0.0020

MetaRNN

Benign

0.018

T;T

MetaSVM

Benign

-0.95

MutationAssessor

Pathogenic

3.7

H;.

MutationTaster

Benign

0.99

N;N;N

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-6.8

D;D

REVEL

Benign

0.11

Sift

Uncertain

0.0030

D;D

Sift4G

Uncertain

0.021

D;D

Polyphen

1.0

D;D

Vest4

0.48

MVP

0.45

MPC

3.8

ClinPred

0.40

GERP RS

-4.7

Varity_R

0.36

gMVP

0.57

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over