10-4995068-T-C

Variant names:

• chr10-4995068-T-C
• rs2801887
• NM_001393392.1:c.846+251A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001393392.1(AKR1C2):​c.846+251A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.95 (25358 hom., cov: 7)
• Consequence: AKR1C2 NM_001393392.1 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.112
• Publications: 0 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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BP6: Variant 10-4995068-T-C is Benign according to our data. Variant chr10-4995068-T-C is described in ClinVar as Benign. ClinVar VariationId is 1259007.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd4 at 25358 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	NM_001393392.1	MANE Select	c.846+251A>G		intron	N/A	NP_001380321.1	P52895-1
	AKR1C2	NM_001354.6		c.846+251A>G		intron	N/A	NP_001345.1	P52895-1
	AKR1C2	NM_205845.3		c.846+251A>G		intron	N/A	NP_995317.1	P52895-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1C2	ENST00000380753.9	TSL:1 MANE Select	c.846+251A>G		intron	N/A	ENSP00000370129.4	P52895-1
	AKR1C2	ENST00000421196.7	TSL:1	c.768+251A>G		intron	N/A	ENSP00000392694.2	B4DK69
	AKR1C2	ENST00000867375.1		c.969+251A>G		intron	N/A	ENSP00000537434.1

Frequencies

GnomAD3 genomes AF: 0.953 AC: 51758 AN: 54314 Hom.: 25340 Cov.: 7

Gnomad AFR AF: 0.832

Gnomad AMI AF: 0.926

Gnomad AMR AF: 0.978

Gnomad ASJ AF: 0.898

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.991

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.942

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.949

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.953 AC: 51799 AN: 54376 Hom.: 25358 Cov.: 7 AF XY: 0.950 AC XY: 23435 AN XY: 24656

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

African (AFR) AF: 0.831 AC: 9848 AN: 11850

American (AMR) AF: 0.978 AC: 4878 AN: 4990

Ashkenazi Jewish (ASJ) AF: 0.898 AC: 997 AN: 1110

East Asian (EAS) AF: 1.00 AC: 1398 AN: 1398

South Asian (SAS) AF: 0.991 AC: 1154 AN: 1164

European-Finnish (FIN) AF: 0.997 AC: 3745 AN: 3758

Middle Eastern (MID) AF: 0.938 AC: 105 AN: 112

European-Non Finnish (NFE) AF: 0.991 AC: 28679 AN: 28936

Other (OTH) AF: 0.949 AC: 619 AN: 652

⚠️ 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: 0.939 Hom.: 886

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	4.2
DANN	Benign	0.39
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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: rs2801887; hg19: chr10-5037260;