Genetic Variant NM_001393392.1:c.666T>C (chr10-4995770-A-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBA1

The NM_001393392.1(AKR1C2):c.666T>C(p.His222His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00262 in 1,596,910 control chromosomes in the GnomAD database, including 85 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.018 ( 47 hom., cov: 27)

Exomes 𝑓: 0.0011 ( 38 hom. )

Consequence

AKR1C2
NM_001393392.1 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter P:1B:2

Conservation

PhyloP100: -4.51

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]

AKR1C2 links:

ENSG00000224251 (HGNC:):

ENSG00000224251 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.96).

BP6

Variant 10-4995770-A-G is Benign according to our data. Variant chr10-4995770-A-G is described in ClinVar as [Benign]. Clinvar id is 805966.Status of the report is criteria_provided_single_submitter, 1 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C2	NM_001393392.1 link	c.666T>C	p.His222His	synonymous_variant	Exon 6 of 9	ENST00000380753.9	NP_001380321.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C2	ENST00000380753.9 link	c.666T>C	p.His222His	synonymous_variant	Exon 6 of 9	1	NM_001393392.1	ENSP00000370129.4		P52895-1

Frequencies

GnomAD3 genomes

AF:

0.0176

AC:

2569

AN:

146338

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0586

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00564

Gnomad ASJ

AF:

0.00349

Gnomad EAS

AF:

0.000802

Gnomad SAS

AF:

0.00113

Gnomad FIN

AF:

0.00109

Gnomad MID

AF:

0.00980

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.0145

GnomAD3 exomes

AF:

0.000236

AC:

AN:

250002

Hom.:

AF XY:

0.000126

AC XY:

AN XY:

135188

show subpopulations

Gnomad AFR exome

AF:

0.00224

Gnomad AMR exome

AF:

0.000262

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000545

Gnomad SAS exome

AF:

0.0000985

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000793

Gnomad OTH exome

AF:

0.000328

GnomAD4 exome

AF:

0.00111

AC:

1606

AN:

1450458

Hom.:

Cov.:

AF XY:

0.00102

AC XY:

737

AN XY:

721284

show subpopulations

Gnomad4 AFR exome

AF:

0.0269

Gnomad4 AMR exome

AF:

0.00189

Gnomad4 ASJ exome

AF:

0.00224

Gnomad4 EAS exome

AF:

0.000252

Gnomad4 SAS exome

AF:

0.000692

Gnomad4 FIN exome

AF:

0.000703

Gnomad4 NFE exome

AF:

0.000283

Gnomad4 OTH exome

AF:

0.00287

GnomAD4 genome

AF:

0.0176

AC:

2584

AN:

146452

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1198

AN XY:

71504

show subpopulations

Gnomad4 AFR

AF:

0.0588

Gnomad4 AMR

AF:

0.00564

Gnomad4 ASJ

AF:

0.00349

Gnomad4 EAS

AF:

0.000804

Gnomad4 SAS

AF:

0.00113

Gnomad4 FIN

AF:

0.00109

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.0144

Alfa

AF:

0.0125

Hom.:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000594

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:2

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

CIC-rearranged sarcoma

Pathogenic:1

Children's Cancer Therapy Development Institute

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:1

May 04, 2022

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

AKR1C2-related disorder

Benign:1

Apr 05, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.96

CADD

Benign

0.11

DANN

Benign

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over