10-4991824-T-C

Variant names:

• chr10-4991824-T-C
• rs200698968
• NM_001393392.1:c.929+7A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001393392.1(AKR1C2):​c.929+7A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.24 (2639 hom., cov: 12)
  • Exomes 𝑓: 0.28 (14526 hom.)
• Consequence: AKR1C2 NM_001393392.1 splice_region, intron
• Scores: Splicing: ADA: 0.00001381
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.17
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 10-4991824-T-C is Benign according to our data. Variant chr10-4991824-T-C is described in ClinVar as Benign. ClinVar VariationId is 1224027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.579 is higher than 0.05.

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.929+7A>G		splice_region intron	N/A	NP_001380321.1	P52895-1
	AKR1C2	NM_001354.6		c.929+7A>G		splice_region intron	N/A	NP_001345.1	P52895-1
	AKR1C2	NM_205845.3		c.929+7A>G		splice_region 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.929+7A>G		splice_region intron	N/A	ENSP00000370129.4	P52895-1
	AKR1C2	ENST00000421196.7	TSL:1	c.851+7A>G		splice_region intron	N/A	ENSP00000392694.2	B4DK69
	AKR1C2	ENST00000867375.1		c.1052+7A>G		splice_region intron	N/A	ENSP00000537434.1

Frequencies

GnomAD3 genomes AF: 0.237 AC: 21123 AN: 89290 Hom.: 2638 Cov.: 12

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.221

Gnomad EAS AF: 0.599

Gnomad SAS AF: 0.441

Gnomad FIN AF: 0.236

Gnomad MID AF: 0.295

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.268

GnomAD2 exomes AF: 0.296 AC: 14564 AN: 49132 AF XY: 0.302

Gnomad AFR exome AF: 0.113

Gnomad AMR exome AF: 0.366

Gnomad ASJ exome AF: 0.151

Gnomad EAS exome AF: 0.600

Gnomad FIN exome AF: 0.225

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.254

GnomAD4 exome AF: 0.276 AC: 98685 AN: 357042 Hom.: 14526 Cov.: 0 AF XY: 0.285 AC XY: 53776 AN XY: 188566

African (AFR) AF: 0.125 AC: 1248 AN: 9964

American (AMR) AF: 0.382 AC: 5495 AN: 14388

Ashkenazi Jewish (ASJ) AF: 0.205 AC: 1992 AN: 9698

East Asian (EAS) AF: 0.594 AC: 15043 AN: 25314

South Asian (SAS) AF: 0.410 AC: 16003 AN: 39068

European-Finnish (FIN) AF: 0.240 AC: 6286 AN: 26178

Middle Eastern (MID) AF: 0.266 AC: 407 AN: 1532

European-Non Finnish (NFE) AF: 0.223 AC: 46942 AN: 210558

Other (OTH) AF: 0.259 AC: 5269 AN: 20342

GnomAD4 genome AF: 0.237 AC: 21136 AN: 89368 Hom.: 2639 Cov.: 12 AF XY: 0.244 AC XY: 9971 AN XY: 40928

African (AFR) AF: 0.134 AC: 2950 AN: 21968

American (AMR) AF: 0.344 AC: 2666 AN: 7740

Ashkenazi Jewish (ASJ) AF: 0.221 AC: 483 AN: 2186

East Asian (EAS) AF: 0.600 AC: 2306 AN: 3844

South Asian (SAS) AF: 0.440 AC: 951 AN: 2160

European-Finnish (FIN) AF: 0.236 AC: 1237 AN: 5244

Middle Eastern (MID) AF: 0.311 AC: 69 AN: 222

European-Non Finnish (NFE) AF: 0.228 AC: 10092 AN: 44194

Other (OTH) AF: 0.271 AC: 315 AN: 1162

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.50
DANN	Benign	0.28
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000014
dbscSNV1_RF	Benign	0.0020
SpliceAI score (max)		0.020		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: rs200698968; hg19: chr10-5034016;