chr10-4830738-G-C

Variant names:

• chr10-4830738-G-C
• rs61745201
• NM_001040177.3:c.103G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001040177.3(AKR1E2):​c.103G>C​(p.Asp35His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D35N) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: AKR1E2 NM_001040177.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.41
• Publications: 11 publications found

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

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.982

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1E2	NM_001040177.3	MANE Select	c.103G>C	p.Asp35His	missense	Exon 2 of 10	NP_001035267.1	Q96JD6-1
	AKR1E2	NM_001271021.2		c.103G>C	p.Asp35His	missense	Exon 2 of 8	NP_001257950.1	Q96JD6-2
	AKR1E2	NM_001271025.2		c.103G>C	p.Asp35His	missense	Exon 2 of 7	NP_001257954.1	Q96JD6-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AKR1E2	ENST00000298375.12	TSL:1 MANE Select	c.103G>C	p.Asp35His	missense	Exon 2 of 10	ENSP00000298375.7	Q96JD6-1
	AKR1E2	ENST00000334019.4	TSL:1	c.103G>C	p.Asp35His	missense	Exon 2 of 8	ENSP00000335034.4	Q96JD6-2
	AKR1E2	ENST00000532248.5	TSL:1	c.103G>C	p.Asp35His	missense	Exon 2 of 7	ENSP00000432947.1	Q96JD6-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.65
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Uncertain	0.060
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.052
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Benign	0.022	T
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.47	D
MutationAssessor	Pathogenic	3.9	H
PhyloP100		7.4
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.32	B
Vest4		0.76
MutPred		0.95		Gain of catalytic residue at C36 (P = 0.0486)
MVP		0.68
MPC		0.46
ClinPred		1.0	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.93
Mutation Taster		=44/56	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs61745201; hg19: chr10-4872930; COSMIC: COSV53629843; COSMIC: COSV53629843;