10-4995393-G-A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001393392.1(AKR1C2):c.772C>T(p.Arg258Cys) 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 Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R258H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 20)
  • Exomes 𝑓: 0.0011 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.60

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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010300577).
• BP6: Variant 10-4995393-G-A is Benign according to our data. Variant chr10-4995393-G-A is described in ClinVar as [Benign]. Clinvar id is 3042249.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1C2	NM_001393392.1	c.772C>T	p.Arg258Cys	missense_variant	7/9	ENST00000380753.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1C2	ENST00000380753.9	c.772C>T	p.Arg258Cys	missense_variant	7/9	1	NM_001393392.1	P1
AKR1C2	ENST00000421196.7	c.694C>T	p.Arg232Cys	missense_variant	6/8	1
AKR1C2	ENST00000460124.5	n.2232C>T		non_coding_transcript_exon_variant	6/8	5

Frequencies

GnomAD3 genomes AF: 0.000148 AC: 22 AN: 148276 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000494

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000633

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00146

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000194

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000497

GnomAD3 exomes AF: 0.00636 AC: 832 AN: 130808 Hom.: 3 AF XY: 0.00529 AC XY: 364 AN XY: 68776

Gnomad AFR exome AF: 0.000307

Gnomad AMR exome AF: 0.0313

Gnomad ASJ exome AF: 0.00217

Gnomad EAS exome AF: 0.0176

Gnomad SAS exome AF: 0.000986

Gnomad FIN exome AF: 0.00373

Gnomad NFE exome AF: 0.000370

Gnomad OTH exome AF: 0.00287

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00113 AC: 1636 AN: 1441716 Hom.: 1 Cov.: 31 AF XY: 0.00100 AC XY: 717 AN XY: 716028

Gnomad4 AFR exome AF: 0.000120

Gnomad4 AMR exome AF: 0.0305

Gnomad4 ASJ exome AF: 0.000896

Gnomad4 EAS exome AF: 0.00609

Gnomad4 SAS exome AF: 0.000235

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.0000580

Gnomad4 OTH exome AF: 0.000556

GnomAD4 genome AF: 0.000148 AC: 22 AN: 148392 Hom.: 0 Cov.: 20 AF XY: 0.000194 AC XY: 14 AN XY: 72094

Gnomad4 AFR AF: 0.0000493

Gnomad4 AMR AF: 0.000632

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00147

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000194

Gnomad4 NFE AF: 0.0000148

Gnomad4 OTH AF: 0.000492

Alfa AF: 0.00130 Hom.: 1

ExAC AF: 0.00844 AC: 933

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

AKR1C2-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2019

This variant is classified as 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
AlphaMissense	Benign	0.25
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.22	T;.
Eigen	Benign	0.052
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.93	D;D
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.78	T
MutationAssessor	Pathogenic	3.9	H;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Uncertain	0.30
Sift	Benign	0.033	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	D;D
Vest4		0.51
MVP		0.44
MPC		3.0
ClinPred		0.095	T
GERP RS		-0.078
Varity_R		0.79
gMVP		0.67

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: rs782195517; hg19: chr10-5037585;