10-5001531-T-C

Position:

• chr10-5001531-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_001393392.1(AKR1C2):​c.235A>G​(p.Ile79Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 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: 33)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.02

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-5001531-T-C is Pathogenic according to our data. Variant chr10-5001531-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 30064.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.28928843). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.235A>G	p.Ile79Val	missense_variant	2/9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.235A>G	p.Ile79Val	missense_variant	2/9	1	NM_001393392.1	ENSP00000370129.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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	Benign	0.12
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	19
DANN	Benign	0.91
DEOGEN2	Benign	0.042	T;.;.;.
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.72	T;T;T;T
M_CAP	Benign	0.0020	T
MetaRNN	Benign	0.29	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.86	L;.;.;L
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.76	N;N;.;N
REVEL	Benign	0.18
Sift	Benign	0.042	D;D;.;T
Sift4G	Benign	0.18	T;T;.;T
Polyphen		0.051	B;B;.;.
Vest4		0.45
MutPred		0.65		Gain of phosphorylation at Y81 (P = 0.135);Gain of phosphorylation at Y81 (P = 0.135);Gain of phosphorylation at Y81 (P = 0.135);Gain of phosphorylation at Y81 (P = 0.135);
MVP		0.12
MPC		0.34
ClinPred		0.30	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.58
gMVP		0.17

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: rs387906750; hg19: chr10-5043723;