1-19306110-C-G

Variant names:

• chr1-19306110-C-G
• NM_003689.4:c.826G>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003689.4(AKR7A2):​c.826G>C​(p.Val276Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AKR7A2 NM_003689.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

Genes affected

AKR7A2 (HGNC:389): (aldo-keto reductase family 7 member A2) The protein encoded by this gene belongs to the aldo/keto reductase (AKR) superfamily and AKR7 family, which are involved in the detoxification of aldehydes and ketones. The AKR7 family consists of 3 genes that are present in a cluster on the p arm of chromosome 1. This protein, thought to be localized in the golgi, catalyzes the NADPH-dependent reduction of succinic semialdehyde to the endogenous neuromodulator, gamma-hydroxybutyrate. It may also function as a detoxication enzyme in the reduction of aflatoxin B1 and 2-carboxybenzaldehyde. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Mar 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38356358).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AKR7A2	NM_003689.4	c.826G>C	p.Val276Leu	missense_variant	Exon 6 of 7	ENST00000235835.8	NP_003680.2
AKR7A2	NM_001320979.1	c.721G>C	p.Val241Leu	missense_variant	Exon 5 of 6		NP_001307908.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AKR7A2	ENST00000235835.8	c.826G>C	p.Val276Leu	missense_variant	Exon 6 of 7	1	NM_003689.4	ENSP00000235835.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.826G>C (p.V276L) alteration is located in exon 6 (coding exon 6) of the AKR7A2 gene. This alteration results from a G to C substitution at nucleotide position 826, causing the valine (V) at amino acid position 276 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	0.31
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.024	T;.
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.065
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.38	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.32	N;.
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.16
Sift	Benign	0.099	T;D
Sift4G	Benign	0.094	T;T
Polyphen		0.11	B;.
Vest4		0.61
MutPred		0.63		Loss of ubiquitination at K278 (P = 0.1179);.;
MVP		0.27
MPC		0.088
ClinPred		0.71	D
GERP RS		3.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-19632604;