10-4826358-T-A

Position:

• chr10-4826358-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001040177.3(AKR1E2):​c.34T>A​(p.Trp12Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKR1E2 NM_001040177.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.914

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AKR1E2	NM_001040177.3	c.34T>A	p.Trp12Arg	missense_variant	1/10	ENST00000298375.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AKR1E2	ENST00000298375.12	c.34T>A	p.Trp12Arg	missense_variant	1/10	1	NM_001040177.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2023

The c.34T>A (p.W12R) alteration is located in exon 1 (coding exon 1) of the AKR1E2 gene. This alteration results from a T to A substitution at nucleotide position 34, causing the tryptophan (W) at amino acid position 12 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.67
BayesDel_addAF	Uncertain	0.076	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.090	T;.;.;.
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.078
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.043	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Benign	-0.88	T
MutationAssessor	Pathogenic	3.3	M;M;M;M
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-11	D;D;D;D
REVEL	Benign	0.25
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.012	D;D;D;D
Polyphen		0.94	P;D;D;P
Vest4		0.66
MutPred		0.76		Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);Gain of disorder (P = 0.003);
MVP		0.34
MPC		0.56
ClinPred		1.0	D
GERP RS		2.8
Varity_R		0.86
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-4868550;