rs3207909

Variant names:

• chr10-4999206-T-C
• rs3207909
• NM_001393392.1:c.441A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001393392.1(AKR1C2):​c.441A>G​(p.Thr147Thr) 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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• 46,XY disorder of sex development due to testicular 17,20-desmolase deficiency

  Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 434114.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.441A>G	p.Thr147Thr	synonymous_variant	Exon 4 of 9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.441A>G	p.Thr147Thr	synonymous_variant	Exon 4 of 9	1	NM_001393392.1	ENSP00000370129.4
AKR1C2	ENST00000421196.7	c.370-459A>G		intron_variant	Intron 3 of 7	1		ENSP00000392694.2
AKR1C2	ENST00000604507.5	c.441A>G	p.Thr147Thr	synonymous_variant	Exon 5 of 7	5		ENSP00000474566.1
AKR1C2	ENST00000460124.5	n.1901A>G		non_coding_transcript_exon_variant	Exon 3 of 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

GnomAD2 exomes AF: 0.221 AC: 40416 AN: 183290 AF XY: 0.226

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 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

African (AFR) AF: 0.0721 AC: 2025 AN: 28078

American (AMR) AF: 0.138 AC: 5106 AN: 36900

Ashkenazi Jewish (ASJ) AF: 0.254 AC: 4903 AN: 19292

East Asian (EAS) AF: 0.0349 AC: 1031 AN: 29548

South Asian (SAS) AF: 0.124 AC: 8186 AN: 65844

European-Finnish (FIN) AF: 0.190 AC: 7886 AN: 41570

Middle Eastern (MID) AF: 0.204 AC: 841 AN: 4124

European-Non Finnish (NFE) AF: 0.267 AC: 231057 AN: 865036

Other (OTH) AF: 0.218 AC: 10337 AN: 47424

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

African (AFR) AF: 0.0670 AC: 2393 AN: 35732

American (AMR) AF: 0.145 AC: 1856 AN: 12776

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 496 AN: 2646

East Asian (EAS) AF: 0.0119 AC: 51 AN: 4294

South Asian (SAS) AF: 0.0798 AC: 319 AN: 3996

European-Finnish (FIN) AF: 0.156 AC: 1357 AN: 8716

Middle Eastern (MID) AF: 0.0955 AC: 21 AN: 220

European-Non Finnish (NFE) AF: 0.211 AC: 11761 AN: 55758

Other (OTH) AF: 0.170 AC: 296 AN: 1742

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

Jul 05, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Nov 11, 2015

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AKR1C2-related disorder Benign:1

Nov 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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
PhyloP100		-9.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3207909; hg19: chr10-5041398; COSMIC: COSV66332774; COSMIC: COSV66332774;