10-4999206-T-C

Position:

• chr10-4999206-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001393392.1(AKR1C2):​c.441A>G​(p.Thr147=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.148 in 126,644 control chromosomes in the GnomAD database, including 1,255 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (1255 hom., cov: 30)
  • Exomes 𝑓: 0.24 (18268 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKR1C2 NM_001393392.1 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -9.11

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]

LOC101928051 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 10-4999206-T-C is Benign according to our data. Variant chr10-4999206-T-C is described in ClinVar as [Benign]. Clinvar id is 434114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-4999206-T-C is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-9.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.208 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.441A>G	p.Thr147=	synonymous_variant	4/9	ENST00000380753.9	NP_001380321.1
LOC101928051	XR_001747340.2	n.2305T>C		non_coding_transcript_exon_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.441A>G	p.Thr147=	synonymous_variant	4/9	1	NM_001393392.1	ENSP00000370129	P1
AKR1C2	ENST00000421196.7	c.370-459A>G		intron_variant		1		ENSP00000392694
AKR1C2	ENST00000604507.5	c.441A>G	p.Thr147=	synonymous_variant	5/7	5		ENSP00000474566
AKR1C2	ENST00000460124.5	n.1901A>G		non_coding_transcript_exon_variant	3/8	5

Frequencies

GnomAD3 genomes AF: 0.148 AC: 18720 AN: 126554 Hom.: 1256 Cov.: 30

Gnomad AFR AF: 0.0672

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.146

Gnomad ASJ AF: 0.187

Gnomad EAS AF: 0.0118

Gnomad SAS AF: 0.0794

Gnomad FIN AF: 0.156

Gnomad MID AF: 0.0984

Gnomad NFE AF: 0.211

Gnomad OTH AF: 0.171

GnomAD3 exomes AF: 0.221 AC: 40416 AN: 183290 Hom.: 1909 AF XY: 0.226 AC XY: 22300 AN XY: 98712

Gnomad AFR exome AF: 0.0870

Gnomad AMR exome AF: 0.144

Gnomad ASJ exome AF: 0.315

Gnomad EAS exome AF: 0.0880

Gnomad SAS exome AF: 0.156

Gnomad FIN exome AF: 0.224

Gnomad NFE exome AF: 0.294

Gnomad OTH exome AF: 0.249

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.239 AC: 271372 AN: 1137816 Hom.: 18268 Cov.: 33 AF XY: 0.236 AC XY: 133205 AN XY: 565314

Gnomad4 AFR exome AF: 0.0721

Gnomad4 AMR exome AF: 0.138

Gnomad4 ASJ exome AF: 0.254

Gnomad4 EAS exome AF: 0.0349

Gnomad4 SAS exome AF: 0.124

Gnomad4 FIN exome AF: 0.190

Gnomad4 NFE exome AF: 0.267

Gnomad4 OTH exome AF: 0.218

GnomAD4 genome AF: 0.148 AC: 18719 AN: 126644 Hom.: 1255 Cov.: 30 AF XY: 0.143 AC XY: 8860 AN XY: 61742

Gnomad4 AFR AF: 0.0670

Gnomad4 AMR AF: 0.145

Gnomad4 ASJ AF: 0.187

Gnomad4 EAS AF: 0.0119

Gnomad4 SAS AF: 0.0798

Gnomad4 FIN AF: 0.156

Gnomad4 NFE AF: 0.211

Gnomad4 OTH AF: 0.170

Alfa AF: 0.197 Hom.: 247

ClinVar

Significance: Benign

Submissions summary: Benign:5

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 05, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Nov 11, 2015

- -

46,XY disorder of sex development due to testicular 17,20-desmolase deficiency Benign:1

Benign, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

AKR1C2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 21, 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
BayesDel_noAF	Benign	-0.93
CADD	Benign	5.0
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs3207909; hg19: chr10-5041398; COSMIC: COSV66332774; COSMIC: COSV66332774;