10-5001629-A-T

Variant names:

• chr10-5001629-A-T
• rs2854482
• NM_001393392.1:c.137T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001393392.1(AKR1C2):​c.137T>A​(p.Phe46Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0379 in 1,613,932 control chromosomes in the GnomAD database, including 1,812 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.065 (548 hom., cov: 33)
  • Exomes 𝑓: 0.035 (1264 hom.)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.35
• Publications: 26 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0024238825).
• BP6: Variant 10-5001629-A-T is Benign according to our data. Variant chr10-5001629-A-T is described in ClinVar as Benign. ClinVar VariationId is 1297289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393392.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	NM_001393392.1	MANE Select	c.137T>A	p.Phe46Tyr	missense	Exon 2 of 9	NP_001380321.1
	AKR1C2	NM_001354.6		c.137T>A	p.Phe46Tyr	missense	Exon 4 of 11	NP_001345.1
	AKR1C2	NM_205845.3		c.137T>A	p.Phe46Tyr	missense	Exon 3 of 10	NP_995317.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	ENST00000380753.9	TSL:1 MANE Select	c.137T>A	p.Phe46Tyr	missense	Exon 2 of 9	ENSP00000370129.4
	AKR1C2	ENST00000421196.7	TSL:1	c.137T>A	p.Phe46Tyr	missense	Exon 2 of 8	ENSP00000392694.2
	AKR1C2	ENST00000604507.5	TSL:5	c.137T>A	p.Phe46Tyr	missense	Exon 3 of 7	ENSP00000474566.1

Frequencies

GnomAD3 genomes AF: 0.0650 AC: 9893 AN: 152144 Hom.: 550 Cov.: 33

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0347

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.00905

Gnomad SAS AF: 0.0234

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0601

Gnomad NFE AF: 0.0346

Gnomad OTH AF: 0.0483

GnomAD2 exomes AF: 0.0371 AC: 9331 AN: 251392 AF XY: 0.0357

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.0186

Gnomad ASJ exome AF: 0.0561

Gnomad EAS exome AF: 0.00816

Gnomad FIN exome AF: 0.0223

Gnomad NFE exome AF: 0.0343

Gnomad OTH exome AF: 0.0376

GnomAD4 exome AF: 0.0351 AC: 51320 AN: 1461670 Hom.: 1264 Cov.: 31 AF XY: 0.0350 AC XY: 25431 AN XY: 727140

African (AFR) AF: 0.160 AC: 5345 AN: 33462

American (AMR) AF: 0.0204 AC: 911 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0563 AC: 1471 AN: 26130

East Asian (EAS) AF: 0.00466 AC: 185 AN: 39696

South Asian (SAS) AF: 0.0279 AC: 2408 AN: 86238

European-Finnish (FIN) AF: 0.0236 AC: 1259 AN: 53420

Middle Eastern (MID) AF: 0.0607 AC: 350 AN: 5766

European-Non Finnish (NFE) AF: 0.0334 AC: 37102 AN: 1111844

Other (OTH) AF: 0.0379 AC: 2289 AN: 60394

GnomAD4 genome AF: 0.0651 AC: 9910 AN: 152262 Hom.: 548 Cov.: 33 AF XY: 0.0622 AC XY: 4632 AN XY: 74460

African (AFR) AF: 0.151 AC: 6257 AN: 41528

American (AMR) AF: 0.0346 AC: 529 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0637 AC: 221 AN: 3470

East Asian (EAS) AF: 0.00907 AC: 47 AN: 5184

South Asian (SAS) AF: 0.0232 AC: 112 AN: 4830

European-Finnish (FIN) AF: 0.0252 AC: 268 AN: 10622

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.0346 AC: 2352 AN: 68014

Other (OTH) AF: 0.0483 AC: 102 AN: 2112

Alfa AF: 0.0394 Hom.: 114

Bravo AF: 0.0689

TwinsUK AF: 0.0283 AC: 105

ALSPAC AF: 0.0397 AC: 153

ESP6500AA AF: 0.138 AC: 610

ESP6500EA AF: 0.0349 AC: 300

ExAC AF: 0.0397 AC: 4820

Asia WGS AF: 0.0260 AC: 92 AN: 3478

EpiCase AF: 0.0350

EpiControl AF: 0.0353

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jul 09, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 21217827, 19258517)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.71	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	13
DANN	Benign	0.52
DEOGEN2	Benign	0.058	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0024	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-2.3	N
PhyloP100		1.4
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.061
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.038	B
Vest4		0.18
MPC		0.60
ClinPred		0.017	T
GERP RS		1.1
Varity_R		0.56
gMVP		0.62
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2854482; hg19: chr10-5043821; COSMIC: COSV108236658; COSMIC: COSV108236658;