Genetic Variant NM_001040177.3:c.257A>G (chr10-4833399-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040177.3(AKR1E2):c.257A>G(p.Lys86Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0425 in 1,614,026 control chromosomes in the GnomAD database, including 1,816 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 Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 149 hom., cov: 32)

Exomes 𝑓: 0.043 ( 1667 hom. )

Consequence

AKR1E2
NM_001040177.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.683

Publications

20 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0043099523).

BP6

Variant 10-4833399-A-G is Benign according to our data. Variant chr10-4833399-A-G is described in ClinVar as Benign. ClinVar VariationId is 1296595.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.107 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1E2	NM_001040177.3 link	c.257A>G	p.Lys86Arg	missense_variant	Exon 3 of 10	ENST00000298375.12	NP_001035267.1	Q96JD6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1E2	ENST00000298375.12 link	c.257A>G	p.Lys86Arg	missense_variant	Exon 3 of 10	1	NM_001040177.3	ENSP00000298375.7		Q96JD6-1

Frequencies

GnomAD3 genomes

AF:

0.0349

AC:

5303

AN:

152158

Hom.:

149

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00975

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.0348

Gnomad ASJ

AF:

0.0132

Gnomad EAS

AF:

0.115

Gnomad SAS

AF:

0.0217

Gnomad FIN

AF:

0.0154

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.0496

Gnomad OTH

AF:

0.0373

GnomAD2 exomes

AF:

0.0399

AC:

10041

AN:

251440

AF XY:

0.0396

show subpopulations

Gnomad AFR exome

AF:

0.00880

Gnomad AMR exome

AF:

0.0315

Gnomad ASJ exome

AF:

0.0164

Gnomad EAS exome

AF:

0.119

Gnomad FIN exome

AF:

0.0148

Gnomad NFE exome

AF:

0.0475

Gnomad OTH exome

AF:

0.0339

GnomAD4 exome

AF:

0.0433

AC:

63339

AN:

1461750

Hom.:

1667

Cov.:

AF XY:

0.0428

AC XY:

31154

AN XY:

727176

show subpopulations

African (AFR)

AF:

0.00702

AC:

235

AN:

33476

American (AMR)

AF:

0.0315

AC:

1408

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0155

AC:

405

AN:

26136

East Asian (EAS)

AF:

0.124

AC:

4935

AN:

39696

South Asian (SAS)

AF:

0.0171

AC:

1475

AN:

86254

European-Finnish (FIN)

AF:

0.0171

AC:

916

AN:

53420

Middle Eastern (MID)

AF:

0.0128

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0465

AC:

51691

AN:

1111898

Other (OTH)

AF:

0.0364

AC:

2200

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

3129

6258

9387

12516

15645

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1890

3780

5670

7560

9450

<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:

0.0348

AC:

5300

AN:

152276

Hom.:

149

Cov.:

AF XY:

0.0331

AC XY:

2466

AN XY:

74448

show subpopulations

African (AFR)

AF:

0.00972

AC:

404

AN:

41558

American (AMR)

AF:

0.0347

AC:

531

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.0132

AC:

AN:

3472

East Asian (EAS)

AF:

0.114

AC:

590

AN:

5170

South Asian (SAS)

AF:

0.0218

AC:

105

AN:

4826

European-Finnish (FIN)

AF:

0.0154

AC:

164

AN:

10620

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0496

AC:

3372

AN:

68010

Other (OTH)

AF:

0.0374

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

254

508

763

1017

1271

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

204

272

340

<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:

0.0449

Hom.:

828

Bravo

AF:

0.0360

TwinsUK

AF:

0.0480

AC:

178

ALSPAC

AF:

0.0519

AC:

200

ESP6500AA

AF:

0.0107

AC:

ESP6500EA

AF:

0.0451

AC:

388

ExAC

AF:

0.0408

AC:

4950

Asia WGS

AF:

0.0540

AC:

187

AN:

3478

EpiCase

AF:

0.0457

EpiControl

AF:

0.0485

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 21, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.61

CADD

Benign

0.84

(source)

DANN

Benign

0.63

DEOGEN2

Benign

0.019

T;T;.;.;.

Eigen

Benign

-1.6

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.11

LIST_S2

Benign

0.66

T;T;T;T;T

MetaRNN

Benign

0.0043

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.71

.;N;N;N;N

PhyloP100

0.68

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.4

N;N;N;N;N

REVEL

Benign

0.064

Sift

Benign

0.21

T;T;T;T;T

Sift4G

Benign

0.39

T;T;T;T;T

Polyphen

0.0010, 0.0

.;B;B;B;B

Vest4

0.032, 0.031, 0.034

MPC

0.063

ClinPred

0.0065

GERP RS

-6.8

Varity_R

0.054

gMVP

0.34

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over