chr10-4995347-T-C

Variant names:

• chr10-4995347-T-C
• rs782501503
• NM_001393392.1:c.818A>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001393392.1(AKR1C2):​c.818A>G​(p.Asn273Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000047 (0 hom., cov: 20)
  • Exomes 𝑓: 0.000082 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: AKR1C2 NM_001393392.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.05

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_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.004617214).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C2	NM_001393392.1	c.818A>G	p.Asn273Ser	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.818A>G	p.Asn273Ser	missense_variant	Exon 7 of 9	1	NM_001393392.1	ENSP00000370129.4
AKR1C2	ENST00000421196.7	c.740A>G	p.Asn247Ser	missense_variant	Exon 6 of 8	1		ENSP00000392694.2
AKR1C2	ENST00000460124.5	n.2278A>G		non_coding_transcript_exon_variant	Exon 6 of 8	5
ENSG00000224251	ENST00000451575.6	n.-141T>C		upstream_gene_variant		3

Frequencies

GnomAD3 genomes AF: 0.0000474 AC: 7 AN: 147686 Hom.: 0 Cov.: 20

Gnomad AFR AF: 0.0000250

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000684

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000694

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000298

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000173 AC: 14 AN: 80882 Hom.: 0 AF XY: 0.000271 AC XY: 11 AN XY: 40562

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000802

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000340

Gnomad SAS exome AF: 0.000876

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0000818 AC: 114 AN: 1393910 Hom.: 0 Cov.: 30 AF XY: 0.000111 AC XY: 76 AN XY: 685762

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000846

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000267

Gnomad4 SAS exome AF: 0.000889

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000269

Gnomad4 OTH exome AF: 0.000208

GnomAD4 genome AF: 0.0000474 AC: 7 AN: 147686 Hom.: 0 Cov.: 20 AF XY: 0.0000558 AC XY: 4 AN XY: 71744

Gnomad4 AFR AF: 0.0000250

Gnomad4 AMR AF: 0.0000684

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000694

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000298

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000340

ExAC AF: 0.0000687 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.818A>G (p.N273S) alteration is located in exon 9 (coding exon 7) of the AKR1C2 gene. This alteration results from a A to G substitution at nucleotide position 818, causing the asparagine (N) at amino acid position 273 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	1.4
DANN	Benign	0.38
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.016	N
LIST_S2	Benign	0.71	T;T
MetaRNN	Benign	0.0046	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.035	N;.
PrimateAI	Benign	0.44	T
PROVEAN	Uncertain	-2.6	D;D
REVEL	Benign	0.019
Sift	Benign	0.27	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0020	B;B
Vest4		0.081
MutPred		0.52		Gain of disorder (P = 0.1044);.;
MVP		0.25
MPC		1.5
ClinPred		0.017	T
GERP RS		-3.3
Varity_R		0.15
gMVP		0.20

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: rs782501503; hg19: chr10-5037539;