chr10-4995401-A-G

Variant names:

• chr10-4995401-A-G
• rs782680340
• NM_001393392.1:c.764T>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_001393392.1(AKR1C2):​c.764T>C​(p.Ile255Thr) variant causes a missense change involving the alteration of a conserved nucleotide. 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: 20)
  • Exomes 𝑓: 0.0000069 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.76

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]

ENSG00000224251 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.807

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.764T>C	p.Ile255Thr	missense_variant	Exon 7 of 9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9	c.764T>C	p.Ile255Thr	missense_variant	Exon 7 of 9	1	NM_001393392.1	ENSP00000370129.4
AKR1C2	ENST00000421196.7	c.686T>C	p.Ile229Thr	missense_variant	Exon 6 of 8	1		ENSP00000392694.2
AKR1C2	ENST00000460124.5	n.2224T>C		non_coding_transcript_exon_variant	Exon 6 of 8	5
ENSG00000224251	ENST00000451575.6	n.-87A>G		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD3 exomes AF: 0.0000145 AC: 2 AN: 137532 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 72422

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000176

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000690 AC: 10 AN: 1449768 Hom.: 0 Cov.: 31 AF XY: 0.00000556 AC XY: 4 AN XY: 719866

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000178

Gnomad4 SAS exome AF: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.04e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

Bravo AF: 0.00000378

ExAC AF: 0.0000801 AC: 9

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T;T
M_CAP	Benign	0.0043	T
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	1.8	L;.
PrimateAI	Uncertain	0.53	T
PROVEAN	Uncertain	-4.2	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.99	D;D
Vest4		0.68
MutPred		0.80		Gain of disorder (P = 0.0311);.;
MVP		0.54
MPC		3.5
ClinPred		0.81	D
GERP RS		3.0
Varity_R		0.83
gMVP		0.53

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: rs782680340; hg19: chr10-5037593;