10-4995770-A-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS2

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 Likely 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/Likely benign criteria provided, multiple submitters, no conflicts P:1B:3

Conservation

PhyloP100: -4.51

Publications

10 publications found

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 Gene-Disease associations (from GenCC):

46,XY disorder of sex development due to testicular 17,20-desmolase deficiency
Inheritance: AR Classification: SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet

AKR1C2 links:

ENSG00000224251 (HGNC:):

ENSG00000224251 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -16 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/Likely_benign. ClinVar VariationId is 805966.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 47 AR gene

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

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

GnomAD2 exomes

AF:

0.000236

AC:

AN:

250002

AF XY:

0.000126

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0269

AC:

867

AN:

32254

American (AMR)

AF:

0.00189

AC:

AN:

44442

Ashkenazi Jewish (ASJ)

AF:

0.00224

AC:

AN:

24952

East Asian (EAS)

AF:

0.000252

AC:

AN:

39646

South Asian (SAS)

AF:

0.000692

AC:

AN:

85312

European-Finnish (FIN)

AF:

0.000703

AC:

AN:

52618

Middle Eastern (MID)

AF:

0.00158

AC:

AN:

5702

European-Non Finnish (NFE)

AF:

0.000283

AC:

313

AN:

1105928

Other (OTH)

AF:

0.00287

AC:

171

AN:

59604

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.321

Heterozygous variant carriers

174

262

349

436

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0176

AC:

2584

AN:

146452

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

1198

AN XY:

71504

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0588

AC:

2355

AN:

40062

American (AMR)

AF:

0.00564

AC:

AN:

14724

Ashkenazi Jewish (ASJ)

AF:

0.00349

AC:

AN:

3148

East Asian (EAS)

AF:

0.000804

AC:

AN:

4974

South Asian (SAS)

AF:

0.00113

AC:

AN:

4428

European-Finnish (FIN)

AF:

0.00109

AC:

AN:

10106

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

284

European-Non Finnish (NFE)

AF:

0.00126

AC:

AN:

65804

Other (OTH)

AF:

0.0144

AC:

AN:

2012

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.352

Heterozygous variant carriers

120

240

359

479

599

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0125

Hom.:

EpiCase

AF:

0.000164

EpiControl

AF:

0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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

46,XY disorder of sex development due to testicular 17,20-desmolase deficiency

Benign:1

Apr 20, 2023

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:research

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

(source)

DANN

Benign

0.45

PhyloP100

-4.5

Mutation Taster

=100/0

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over