10-4998642-T-C

Variant names:

• chr10-4998642-T-C
• rs2518043
• NM_001393392.1:c.553A>G

Variant summary

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

The NM_001393392.1(AKR1C2):​c.553A>G​(p.Lys185Glu) 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: 5.20
• Publications: 10 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.553A>G	p.Lys185Glu	missense_variant	Exon 5 of 9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.553A>G	p.Lys185Glu	missense_variant	Exon 5 of 9	1	NM_001393392.1	ENSP00000370129.4
AKR1C2	ENST00000421196.7	c.475A>G	p.Lys159Glu	missense_variant	Exon 4 of 8	1		ENSP00000392694.2
AKR1C2	ENST00000604507.5	c.553A>G	p.Lys185Glu	missense_variant	Exon 6 of 7	5		ENSP00000474566.1
AKR1C2	ENST00000460124.5	n.2013A>G		non_coding_transcript_exon_variant	Exon 4 of 8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Benign	0.73	D
LIST_S2	Uncertain	0.97	D;T;D
M_CAP	Benign	0.0049	T
MetaRNN	Uncertain	0.68	D;D;D
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.7	L;.;.
PhyloP100		5.2
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.8	D;D;.
REVEL	Benign	0.23
Sift	Uncertain	0.0050	D;D;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;D;.
Vest4		0.74
MutPred		0.66		Loss of methylation at K185 (P = 0.0228);.;Loss of methylation at K185 (P = 0.0228);
MVP		0.38
MPC		0.61
ClinPred		0.99	D
GERP RS		3.0
Varity_R		0.93
gMVP		0.44
Mutation Taster		=66/34	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: rs2518043; hg19: chr10-5040834;