chr10-4830738-G-A

Position:

• chr10-4830738-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_001040177.3(AKR1E2):​c.103G>A​(p.Asp35Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0629 in 1,613,988 control chromosomes in the GnomAD database, including 3,594 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (262 hom., cov: 32)
  • Exomes 𝑓: 0.064 (3332 hom.)
• Consequence: AKR1E2 NM_001040177.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 7.41

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• PM1: In a binding_site (size 0) in uniprot entity AKCL2_HUMAN
• BP4: Computational evidence support a benign effect (MetaRNN=0.004357338).
• BP6: Variant 10-4830738-G-A is Benign according to our data. Variant chr10-4830738-G-A is described in ClinVar as [Benign]. Clinvar id is 677203.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0671 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1E2	NM_001040177.3	c.103G>A	p.Asp35Asn	missense_variant	2/10	ENST00000298375.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1E2	ENST00000298375.12	c.103G>A	p.Asp35Asn	missense_variant	2/10	1	NM_001040177.3	P1

Frequencies

GnomAD3 genomes AF: 0.0519 AC: 7896 AN: 152058 Hom.: 262 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.162

Gnomad AMR AF: 0.0309

Gnomad ASJ AF: 0.0383

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0238

Gnomad FIN AF: 0.0815

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0688

Gnomad OTH AF: 0.0450

GnomAD3 exomes AF: 0.0518 AC: 13035 AN: 251466 Hom.: 434 AF XY: 0.0514 AC XY: 6987 AN XY: 135910

Gnomad AFR exome AF: 0.0346

Gnomad AMR exome AF: 0.0253

Gnomad ASJ exome AF: 0.0391

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0271

Gnomad FIN exome AF: 0.0888

Gnomad NFE exome AF: 0.0715

Gnomad OTH exome AF: 0.0526

GnomAD4 exome AF: 0.0641 AC: 93653 AN: 1461812 Hom.: 3332 Cov.: 31 AF XY: 0.0629 AC XY: 45751 AN XY: 727206

Gnomad4 AFR exome AF: 0.0372

Gnomad4 AMR exome AF: 0.0266

Gnomad4 ASJ exome AF: 0.0393

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0265

Gnomad4 FIN exome AF: 0.0895

Gnomad4 NFE exome AF: 0.0715

Gnomad4 OTH exome AF: 0.0568

GnomAD4 genome AF: 0.0519 AC: 7900 AN: 152176 Hom.: 262 Cov.: 32 AF XY: 0.0508 AC XY: 3781 AN XY: 74400

Gnomad4 AFR AF: 0.0333

Gnomad4 AMR AF: 0.0309

Gnomad4 ASJ AF: 0.0383

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0239

Gnomad4 FIN AF: 0.0815

Gnomad4 NFE AF: 0.0688

Gnomad4 OTH AF: 0.0445

Alfa AF: 0.0622 Hom.: 491

Bravo AF: 0.0488

TwinsUK AF: 0.0696 AC: 258

ALSPAC AF: 0.0623 AC: 240

ESP6500AA AF: 0.0354 AC: 156

ESP6500EA AF: 0.0658 AC: 566

ExAC AF: 0.0544 AC: 6604

Asia WGS AF: 0.0130 AC: 45 AN: 3478

EpiCase AF: 0.0609

EpiControl AF: 0.0655

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 17, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.17	T;T;.;.;.
Eigen	Benign	-0.070
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.91	D;D;D;D;D
MetaRNN	Benign	0.0044	T;T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Pathogenic	4.1	.;H;H;H;H
MutationTaster	Benign	0.00018	P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.5	D;D;D;D;D
REVEL	Uncertain	0.36
Sift	Uncertain	0.010	D;D;D;D;D
Sift4G	Uncertain	0.017	D;D;D;D;D
Polyphen		0.090, 0.67, 0.57, 0.28	.;B;P;P;B
Vest4		0.25, 0.15, 0.24, 0.18
MPC		0.16
ClinPred		0.10	T
GERP RS		3.0
Varity_R		0.62
gMVP		0.92

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

LitVar

Other links and lift over

dbSNP: rs61745201; hg19: chr10-4872930;