rs797044460

Positions:

• chr10-5000649-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP5

The NM_001393392.1(AKR1C2):​c.270T>G​(p.His90Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: -0.0220

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-5000649-A-C is Pathogenic according to our data. Variant chr10-5000649-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 30065.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.270T>G	p.His90Gln	missense_variant	3/9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.270T>G	p.His90Gln	missense_variant	3/9	1	NM_001393392.1	ENSP00000370129.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 12, 2011

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Benign	-0.018	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	11
DANN	Uncertain	0.98
DEOGEN2	Benign	0.14	T;.;.;.
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.78	T;D;T;D
M_CAP	Benign	0.0039	T
MetaRNN	Uncertain	0.60	D;D;D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.85	L;.;.;L
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-4.0	D;D;.;D
REVEL	Benign	0.25
Sift	Benign	0.095	T;T;.;T
Sift4G	Uncertain	0.012	D;D;.;D
Polyphen		0.16	B;P;.;.
Vest4		0.20
MutPred		0.69		Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);Gain of solvent accessibility (P = 0.0338);
MVP		0.54
MPC		0.56
ClinPred		0.88	D
GERP RS		0.49
Varity_R		0.46
gMVP		0.51

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

Publications

LitVar

Other links and lift over

dbSNP: rs797044460; hg19: chr10-5042841;