10-4995393-G-C

Variant names:

• chr10-4995393-G-C
• NM_001393392.1:c.772C>G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001393392.1(AKR1C2):​c.772C>G​(p.Arg258Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,972 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.

• Frequency:
  • Genomes: not found (cov: 20)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.772C>G	p.Arg258Gly	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.772C>G	p.Arg258Gly	missense_variant	Exon 7 of 9	1	NM_001393392.1	ENSP00000370129.4
AKR1C2	ENST00000421196.7	c.694C>G	p.Arg232Gly	missense_variant	Exon 6 of 8	1		ENSP00000392694.2
AKR1C2	ENST00000460124.5	n.2232C>G		non_coding_transcript_exon_variant	Exon 6 of 8	5
ENSG00000224251	ENST00000451575.6	n.-95G>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 20

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1444972 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 717448

Gnomad4 AFR exome AF: 0.0000301

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 20

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	0.0069
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Pathogenic	0.99	D;D
M_CAP	Benign	0.0037	T
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.1	M;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.6	D;D
REVEL	Uncertain	0.39
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		1.0	D;D
Vest4		0.77
MutPred		0.86		Loss of MoRF binding (P = 0.0203);.;
MVP		0.36
MPC		3.6
ClinPred		1.0	D
GERP RS		-0.078
Varity_R		0.96
gMVP		0.71

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: chr10-5037585;