rs2518042

Variant names:

• chr10-4998660-T-C
• rs2518042
• NM_001393392.1:c.535A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001393392.1(AKR1C2):​c.535A>G​(p.Lys179Glu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.30
• Publications: 2 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	NM_001393392.1	MANE Select	c.535A>G	p.Lys179Glu	missense	Exon 5 of 9	NP_001380321.1	P52895-1
	AKR1C2	NM_001354.6		c.535A>G	p.Lys179Glu	missense	Exon 7 of 11	NP_001345.1	P52895-1
	AKR1C2	NM_205845.3		c.535A>G	p.Lys179Glu	missense	Exon 6 of 10	NP_995317.1	P52895-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	ENST00000380753.9	TSL:1 MANE Select	c.535A>G	p.Lys179Glu	missense	Exon 5 of 9	ENSP00000370129.4	P52895-1
	AKR1C2	ENST00000421196.7	TSL:1	c.457A>G	p.Lys153Glu	missense	Exon 4 of 8	ENSP00000392694.2	B4DK69
	AKR1C2	ENST00000867375.1		c.658A>G	p.Lys220Glu	missense	Exon 6 of 10	ENSP00000537434.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00 AC: 0 AN: 251474 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000658 Hom.: 0

Bravo AF: 0.0000151

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.44
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Benign	0.072
Eigen_PC	Benign	-0.025
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.85	D
M_CAP	Benign	0.0035	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.17	N
PhyloP100		5.3
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-3.8	D
REVEL	Benign	0.20
Sift	Uncertain	0.0060	D
Sift4G	Benign	0.20	T
Polyphen		0.98	D
Vest4		0.43
MVP		0.30
MPC		0.56
ClinPred		0.96	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.93
gMVP		0.21
Mutation Taster		=69/31	polymorphism

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: rs2518042; hg19: chr10-5040852;