rs17134592

Variant names:

• chr10-5218719-C-G
• rs17134592
• NM_001818.5:c.931C>G

Your query was ambiguous. Multiple possible variants found:

• chr10-5218719-C-G
• chr10-5218719-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001818.5(AKR1C4):​c.931C>G​(p.Leu311Val) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.139 in 1,593,568 control chromosomes in the GnomAD database, including 16,529 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/23 in silico tools predict 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L311R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.11 (1185 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15344 hom.)
• Consequence: AKR1C4 NM_001818.5 missense, splice_region
• Scores: Splicing: ADA: 0.00002144
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.50
• Publications: 43 publications found

Genes affected

AKR1C4 (HGNC:387): (aldo-keto reductase family 1 member C4) 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 by utilizing NADH and/or NADPH as cofactors. The enzymes display overlapping but distinct substrate specificity. This enzyme catalyzes the bioreduction of chlordecone, a toxic organochlorine pesticide, to chlordecone alcohol in liver. This gene shares high sequence identity with three other gene members and is clustered with those three genes at chromosome 10p15-p14. [provided by RefSeq, Jul 2008]

AKR1C4 Gene-Disease associations (from GenCC):

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

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.010312349).
• BP6: Variant 10-5218719-C-G is Benign according to our data. Variant chr10-5218719-C-G is described in ClinVar as Benign. ClinVar VariationId is 2017866.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1C4	NM_001818.5	c.931C>G	p.Leu311Val	missense_variant, splice_region_variant	Exon 9 of 9	ENST00000263126.3	NP_001809.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1C4	ENST00000263126.3	c.931C>G	p.Leu311Val	missense_variant, splice_region_variant	Exon 9 of 9	1	NM_001818.5	ENSP00000263126.1
AKR1C4	ENST00000380448.5	c.931C>G	p.Leu311Val	missense_variant, splice_region_variant	Exon 11 of 11	5		ENSP00000369814.1

Frequencies

GnomAD3 genomes AF: 0.113 AC: 17147 AN: 152034 Hom.: 1182 Cov.: 32

Gnomad AFR AF: 0.0382

Gnomad AMI AF: 0.0936

Gnomad AMR AF: 0.166

Gnomad ASJ AF: 0.105

Gnomad EAS AF: 0.101

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.147

Gnomad OTH AF: 0.104

GnomAD2 exomes AF: 0.136 AC: 34141 AN: 250340 AF XY: 0.135

Gnomad AFR exome AF: 0.0360

Gnomad AMR exome AF: 0.201

Gnomad ASJ exome AF: 0.103

Gnomad EAS exome AF: 0.104

Gnomad FIN exome AF: 0.126

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.143

GnomAD4 exome AF: 0.141 AC: 203908 AN: 1441416 Hom.: 15344 Cov.: 30 AF XY: 0.140 AC XY: 100360 AN XY: 718294

African (AFR) AF: 0.0321 AC: 1065 AN: 33130

American (AMR) AF: 0.202 AC: 9024 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0981 AC: 2552 AN: 26016

East Asian (EAS) AF: 0.0897 AC: 3549 AN: 39570

South Asian (SAS) AF: 0.104 AC: 8887 AN: 85836

European-Finnish (FIN) AF: 0.134 AC: 7139 AN: 53324

Middle Eastern (MID) AF: 0.0744 AC: 427 AN: 5738

European-Non Finnish (NFE) AF: 0.149 AC: 163445 AN: 1093440

Other (OTH) AF: 0.131 AC: 7820 AN: 59732

GnomAD4 genome AF: 0.113 AC: 17163 AN: 152152 Hom.: 1185 Cov.: 32 AF XY: 0.113 AC XY: 8388 AN XY: 74380

African (AFR) AF: 0.0381 AC: 1582 AN: 41532

American (AMR) AF: 0.167 AC: 2551 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.105 AC: 365 AN: 3464

East Asian (EAS) AF: 0.102 AC: 527 AN: 5174

South Asian (SAS) AF: 0.106 AC: 511 AN: 4818

European-Finnish (FIN) AF: 0.123 AC: 1302 AN: 10586

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.147 AC: 10001 AN: 68000

Other (OTH) AF: 0.102 AC: 214 AN: 2108

Alfa AF: 0.115 Hom.: 425

Bravo AF: 0.114

TwinsUK AF: 0.170 AC: 629

ALSPAC AF: 0.164 AC: 631

ESP6500AA AF: 0.0420 AC: 185

ESP6500EA AF: 0.151 AC: 1301

ExAC AF: 0.136 AC: 16478

Asia WGS AF: 0.0910 AC: 317 AN: 3478

EpiCase AF: 0.140

EpiControl AF: 0.142

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.82	T
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.020
DANN	Benign	0.21
DEOGEN2	Benign	0.040	T;T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.8
FATHMM_MKL	Benign	0.00098	N
LIST_S2	Benign	0.29	.;T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.81	L;L
PhyloP100		-2.5
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.67	N;N
REVEL	Benign	0.010
Sift	Benign	0.45	T;T
Sift4G	Benign	0.52	T;T
Polyphen		0.0	B;B
Vest4		0.041
MPC		0.015
ClinPred		0.0016	T
GERP RS		-5.7
Varity_R		0.12
gMVP		0.14
Mutation Taster		=82/18	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.0020
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: rs17134592; hg19: chr10-5260682; COSMIC: COSV54122788;