chr10-4995770-A-G

Variant names:

• chr10-4995770-A-G
• rs13222
• NM_001393392.1:c.666T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1 B:3
• Conservation: PhyloP100: -4.51
• Publications: 10 publications found

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

ENSG00000224251 (HGNC:):

ACMG classification

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001393392.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	NM_001393392.1	MANE Select	c.666T>C	p.His222His	synonymous	Exon 6 of 9	NP_001380321.1
	AKR1C2	NM_001354.6		c.666T>C	p.His222His	synonymous	Exon 8 of 11	NP_001345.1
	AKR1C2	NM_205845.3		c.666T>C	p.His222His	synonymous	Exon 7 of 10	NP_995317.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	ENST00000380753.9	TSL:1 MANE Select	c.666T>C	p.His222His	synonymous	Exon 6 of 9	ENSP00000370129.4
	AKR1C2	ENST00000421196.7	TSL:1	c.588T>C	p.His196His	synonymous	Exon 5 of 8	ENSP00000392694.2
	AKR1C2	ENST00000460124.5	TSL:5	n.2126T>C		non_coding_transcript_exon	Exon 5 of 8

Frequencies

GnomAD3 genomes AF: 0.0176 AC: 2569 AN: 146338 Hom.: 44 Cov.: 27

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: 59 AN: 250002 AF XY: 0.000126

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.: 38 Cov.: 32 AF XY: 0.00102 AC XY: 737 AN XY: 721284

⚠️ 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: 84 AN: 44442

Ashkenazi Jewish (ASJ) AF: 0.00224 AC: 56 AN: 24952

East Asian (EAS) AF: 0.000252 AC: 10 AN: 39646

South Asian (SAS) AF: 0.000692 AC: 59 AN: 85312

European-Finnish (FIN) AF: 0.000703 AC: 37 AN: 52618

Middle Eastern (MID) AF: 0.00158 AC: 9 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.

GnomAD4 genome AF: 0.0176 AC: 2584 AN: 146452 Hom.: 47 Cov.: 27 AF XY: 0.0168 AC XY: 1198 AN XY: 71504

⚠️ 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: 83 AN: 14724

Ashkenazi Jewish (ASJ) AF: 0.00349 AC: 11 AN: 3148

East Asian (EAS) AF: 0.000804 AC: 4 AN: 4974

South Asian (SAS) AF: 0.00113 AC: 5 AN: 4428

European-Finnish (FIN) AF: 0.00109 AC: 11 AN: 10106

Middle Eastern (MID) AF: 0.0106 AC: 3 AN: 284

European-Non Finnish (NFE) AF: 0.00126 AC: 83 AN: 65804

Other (OTH) AF: 0.0144 AC: 29 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.

Alfa AF: 0.0125 Hom.: 4

EpiCase AF: 0.000164

EpiControl AF: 0.0000594

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1 Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.11
DANN	Benign	0.45
PhyloP100		-4.5
Mutation Taster		=100/0	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs13222; hg19: chr10-5037962; COSMIC: COSV66332725; COSMIC: COSV66332725;