12-6917622-G-A

Variant names:

• chr12-6917622-G-A
• rs374122047
• NM_001975.3:c.352G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001975.3(ENO2):​c.352G>A​(p.Val118Met) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,613,530 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V118L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00012 (0 hom.)
• Consequence: ENO2 NM_001975.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98
• Publications: 2 publications found

Genes affected

ENO2 (HGNC:3353): (enolase 2) This gene encodes one of the three enolase isoenzymes found in mammals. This isoenzyme, a homodimer, is found in mature neurons and cells of neuronal origin. A switch from alpha enolase to gamma enolase occurs in neural tissue during development in rats and primates. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENO2	NM_001975.3	c.352G>A	p.Val118Met	missense_variant	Exon 6 of 12	ENST00000229277.6	NP_001966.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENO2	ENST00000229277.6	c.352G>A	p.Val118Met	missense_variant	Exon 6 of 12	1	NM_001975.3	ENSP00000229277.1

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000104 AC: 26 AN: 250624 AF XY: 0.000103

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.000400

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000141

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000118 AC: 173 AN: 1461350 Hom.: 0 Cov.: 32 AF XY: 0.000128 AC XY: 93 AN XY: 726986

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000112 AC: 5 AN: 44688

Ashkenazi Jewish (ASJ) AF: 0.000192 AC: 5 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86222

European-Finnish (FIN) AF: 0.0000751 AC: 4 AN: 53286

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5764

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111764

Other (OTH) AF: 0.000215 AC: 13 AN: 60374

GnomAD4 genome AF: 0.000131 AC: 20 AN: 152180 Hom.: 0 Cov.: 32 AF XY: 0.000121 AC XY: 9 AN XY: 74348

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.000327 AC: 5 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68016

Other (OTH) AF: 0.00191 AC: 4 AN: 2092

Alfa AF: 0.000255 Hom.: 0

Bravo AF: 0.000113

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.0000577 AC: 7

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.352G>A (p.V118M) alteration is located in exon 6 (coding exon 5) of the ENO2 gene. This alteration results from a G to A substitution at nucleotide position 352, causing the valine (V) at amino acid position 118 to be replaced by a methionine (M). 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	0.28
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T;T;.;T
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.97	.;D;D;.
M_CAP	Benign	0.063	D
MetaRNN	Uncertain	0.69	D;D;D;D
MetaSVM	Uncertain	-0.0083	T
MutationAssessor	Pathogenic	4.3	H;H;.;H
PhyloP100		4.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-2.5	D;D;N;D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0010	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.75
MVP		0.73
MPC		1.5
ClinPred		0.96	D
GERP RS		3.9
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.60
gMVP		0.65
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

dbSNP: rs374122047; hg19: chr12-7026786;