rs2854482

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001393392.1(AKR1C2):​c.137T>C​(p.Phe46Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,684 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. F46Y) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

AKR1C2
NM_001393392.1 missense

Scores

5
2
12

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.35
Variant links:
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]

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ACMG classification

Classification made for transcript

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, 0.828

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
AKR1C2NM_001393392.1 linkc.137T>C p.Phe46Ser missense_variant Exon 2 of 9 ENST00000380753.9 NP_001380321.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
AKR1C2ENST00000380753.9 linkc.137T>C p.Phe46Ser missense_variant Exon 2 of 9 1 NM_001393392.1 ENSP00000370129.4 P52895-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461684
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727146
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.95
BayesDel_addAF
Benign
-0.087
T
BayesDel_noAF
Benign
-0.36
CADD
Benign
22
DANN
Uncertain
0.99
DEOGEN2
Benign
0.20
T;.;.;.
Eigen
Benign
-0.14
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.59
D
LIST_S2
Benign
0.82
T;T;T;T
M_CAP
Benign
0.0025
T
MetaRNN
Pathogenic
0.83
D;D;D;D
MetaSVM
Benign
-0.91
T
MutationAssessor
Benign
0.94
L;.;.;L
PrimateAI
Uncertain
0.49
T
PROVEAN
Pathogenic
-6.9
D;D;.;D
REVEL
Benign
0.18
Sift
Pathogenic
0.0
D;D;.;D
Sift4G
Pathogenic
0.0
D;D;.;D
Polyphen
1.0
D;D;.;.
Vest4
0.56
MutPred
0.71
Gain of disorder (P = 0.0021);Gain of disorder (P = 0.0021);Gain of disorder (P = 0.0021);Gain of disorder (P = 0.0021);
MVP
0.39
MPC
0.76
ClinPred
0.91
D
GERP RS
1.1
Varity_R
0.96
gMVP
0.77

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-5043821; API