10-4826343-G-C

Variant names:

• chr10-4826343-G-C
• rs1588423019
• NM_001040177.3:c.19G>C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001040177.3(AKR1E2):​c.19G>C​(p.Val7Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000924 in 1,082,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 9.2e-7 (0 hom.)
• Consequence: AKR1E2 NM_001040177.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.982

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.11170566).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR1E2	NM_001040177.3	c.19G>C	p.Val7Leu	missense_variant	Exon 1 of 10	ENST00000298375.12	NP_001035267.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR1E2	ENST00000298375.12	c.19G>C	p.Val7Leu	missense_variant	Exon 1 of 10	1	NM_001040177.3	ENSP00000298375.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 9.24e-7 AC: 1 AN: 1082706 Hom.: 0 Cov.: 32 AF XY: 0.00000195 AC XY: 1 AN XY: 511536

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000109

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 27, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.19G>C (p.V7L) alteration is located in exon 1 (coding exon 1) of the AKR1E2 gene. This alteration results from a G to C substitution at nucleotide position 19, causing the valine (V) at amino acid position 7 to be replaced by a leucine (L). 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	Benign	0.18
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.79
CADD	Benign	0.45
DANN	Benign	0.61
DEOGEN2	Benign	0.0019	T;.;.;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.035	N
LIST_S2	Uncertain	0.88	D;D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.11	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.42	N;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.28	N;N;N;N
REVEL	Benign	0.058
Sift	Benign	1.0	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0070	B;B;B;B
Vest4		0.089
MutPred		0.66		Gain of disorder (P = 0.172);Gain of disorder (P = 0.172);Gain of disorder (P = 0.172);Gain of disorder (P = 0.172);
MVP		0.030
MPC		0.081
ClinPred		0.087	T
GERP RS		-4.2
Varity_R		0.13
gMVP		0.60

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

LitVar

Other links and lift over

dbSNP: rs1588423019; hg19: chr10-4868535;