rs2854486

Positions:

• chr10-5000587-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001393392.1(AKR1C2):​c.332T>C​(p.Val111Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 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: 6.30

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
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.838

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.332T>C	p.Val111Ala	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.332T>C	p.Val111Ala	missense_variant	3/9	1	NM_001393392.1	ENSP00000370129.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.000310 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.;.
Eigen	Benign	0.15
Eigen_PC	Benign	0.064
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.0079	T
MetaRNN	Pathogenic	0.84	D;D;D;D
MetaSVM	Benign	-0.34	T
MutationAssessor	Benign	1.9	L;.;.;L
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.5	D;D;.;D
REVEL	Benign	0.28
Sift	Uncertain	0.029	D;D;.;D
Sift4G	Uncertain	0.0070	D;D;.;D
Polyphen		0.10	B;P;.;.
Vest4		0.53
MutPred		0.68		Loss of stability (P = 9e-04);Loss of stability (P = 9e-04);Loss of stability (P = 9e-04);Loss of stability (P = 9e-04);
MVP		0.66
MPC		0.39
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.62
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs2854486; hg19: chr10-5042779;