Genetic Variant AKR1E2:p.Cys52Gly (chr10-4830789-T-G) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001040177.3(AKR1E2):c.154T>G(p.Cys52Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000903 in 1,614,140 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C52R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0050 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00047 ( 5 hom. )

Consequence

AKR1E2
NM_001040177.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.886

Publications

1 publications found

Variant links:

Genes affected

AKR1E2 (HGNC:23437): (aldo-keto reductase family 1 member E2) The protein encoded by this gene is a member of the aldo-keto reductase superfamily. Members in this family are characterized by their structure (evolutionarily highly conserved TIM barrel) and function (NAD(P)H-dependent oxido-reduction of carbonyl groups). Transcripts of this gene have been reported in specimens of human testis. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2012]

AKR1E2 Gene-Disease associations (from GenCC):

cataract
Inheritance: AR Classification: LIMITED Submitted by: G2P

AKR1E2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.006289184).

BP6

Variant 10-4830789-T-G is Benign according to our data. Variant chr10-4830789-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1693334.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00503 (766/152262) while in subpopulation AFR AF = 0.0179 (742/41540). AF 95% confidence interval is 0.0168. There are 8 homozygotes in GnomAd4. There are 314 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040177.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AKR1E2	NM_001040177.3	MANE Select	c.154T>G	p.Cys52Gly	missense	Exon 2 of 10	NP_001035267.1	Q96JD6-1
AKR1E2	NM_001271021.2		c.154T>G	p.Cys52Gly	missense	Exon 2 of 8	NP_001257950.1	Q96JD6-2
AKR1E2	NM_001271025.2		c.154T>G	p.Cys52Gly	missense	Exon 2 of 7	NP_001257954.1	Q96JD6-5

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
AKR1E2	ENST00000298375.12	TSL:1 MANE Select	c.154T>G	p.Cys52Gly	missense	Exon 2 of 10	ENSP00000298375.7	Q96JD6-1
AKR1E2	ENST00000334019.4	TSL:1	c.154T>G	p.Cys52Gly	missense	Exon 2 of 8	ENSP00000335034.4	Q96JD6-2
AKR1E2	ENST00000532248.5	TSL:1	c.154T>G	p.Cys52Gly	missense	Exon 2 of 7	ENSP00000432947.1	Q96JD6-3

Frequencies

GnomAD3 genomes

AF:

0.00503

AC:

765

AN:

152144

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0179

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00111

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00120

AC:

301

AN:

251476

AF XY:

0.000861

show subpopulations

Gnomad AFR exome

AF:

0.0170

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000473

AC:

692

AN:

1461878

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727240

show subpopulations

African (AFR)

AF:

0.0180

AC:

602

AN:

33480

American (AMR)

AF:

0.000581

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1112002

Other (OTH)

AF:

0.000729

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

116

154

193

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:

0.00503

AC:

766

AN:

152262

Hom.:

Cov.:

AF XY:

0.00422

AC XY:

314

AN XY:

74454

show subpopulations

African (AFR)

AF:

0.0179

AC:

742

AN:

41540

American (AMR)

AF:

0.00111

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68028

Other (OTH)

AF:

0.00284

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

109

146

182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00185

Hom.:

Bravo

AF:

0.00592

ESP6500AA

AF:

0.0166

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00158

AC:

192

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.29

(source)

DANN

Benign

0.52

DEOGEN2

Benign

0.018

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.6

FATHMM_MKL

Benign

0.024

LIST_S2

Benign

0.69

MetaRNN

Benign

0.0063

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-1.1

PhyloP100

-0.89

PrimateAI

Benign

0.27

PROVEAN

Benign

-1.5

REVEL

Benign

0.039

Sift

Benign

0.10

Sift4G

Benign

0.12

Polyphen

0.0

Vest4

0.30

MVP

0.16

MPC

0.10

ClinPred

0.0023

GERP RS

-8.0

Varity_R

0.058

gMVP

0.48

Mutation Taster

=100/0

polymorphism

(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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over