12-111803962-G-A

Position:

chr12-111803962-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000690.4(ALDH2):c.1510G>A(p.Glu504Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00704 in 1,608,410 control chromosomes in the GnomAD database, including 1,380 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as drug response (★★★).

Frequency

Genomes: 𝑓 0.0078 ( 141 hom., cov: 31)

Exomes 𝑓: 0.0070 ( 1239 hom. )

Consequence

ALDH2
NM_000690.4 missense

Scores

Clinical Significance

drug response reviewed by expert panel P:1B:1O:5

Conservation

PhyloP100: 9.78

Variant links:

Genes affected

ALDH2 (HGNC:404): (aldehyde dehydrogenase 2 family member) This protein belongs to the aldehyde dehydrogenase family of proteins. Aldehyde dehydrogenase is the second enzyme of the major oxidative pathway of alcohol metabolism. Two major liver isoforms of aldehyde dehydrogenase, cytosolic and mitochondrial, can be distinguished by their electrophoretic mobilities, kinetic properties, and subcellular localizations. Most Caucasians have two major isozymes, while approximately 50% of East Asians have the cytosolic isozyme but not the mitochondrial isozyme. A remarkably higher frequency of acute alcohol intoxication among East Asians than among Caucasians could be related to the absence of a catalytically active form of the mitochondrial isozyme. The increased exposure to acetaldehyde in individuals with the catalytically inactive form may also confer greater susceptibility to many types of cancer. This gene encodes a mitochondrial isoform, which has a low Km for acetaldehydes, and is localized in mitochondrial matrix. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Nov 2016]

ALDH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.001886636).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.214 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH2	NM_000690.4 linkuse as main transcript	c.1510G>A	p.Glu504Lys	missense_variant	12/13	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2 linkuse as main transcript	c.1369G>A	p.Glu457Lys	missense_variant	11/12		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7 linkuse as main transcript	c.1510G>A	p.Glu504Lys	missense_variant	12/13	1	NM_000690.4	ENSP00000261733	P1	P05091-1
ALDH2	ENST00000416293.7 linkuse as main transcript	c.1369G>A	p.Glu457Lys	missense_variant	11/12	2		ENSP00000403349		P05091-2
ALDH2	ENST00000548536.1 linkuse as main transcript	c.*1386G>A		3_prime_UTR_variant, NMD_transcript_variant	13/14	3		ENSP00000448179
ALDH2	ENST00000549106.1 linkuse as main transcript	c.*89G>A		3_prime_UTR_variant, NMD_transcript_variant	3/4	3		ENSP00000474669

Frequencies

GnomAD3 genomes

AF:

0.00787

AC:

1196

AN:

152056

Hom.:

141

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000918

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.225

Gnomad SAS

AF:

0.000829

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00527

GnomAD3 exomes

AF:

0.0189

AC:

4582

AN:

242666

Hom.:

590

AF XY:

0.0176

AC XY:

2310

AN XY:

131478

show subpopulations

Gnomad AFR exome

AF:

0.000194

Gnomad AMR exome

AF:

0.000390

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.254

Gnomad SAS exome

AF:

0.000270

Gnomad FIN exome

AF:

0.0000471

Gnomad NFE exome

AF:

0.0000274

Gnomad OTH exome

AF:

0.00555

GnomAD4 exome

AF:

0.00695

AC:

10123

AN:

1456236

Hom.:

1239

Cov.:

AF XY:

0.00689

AC XY:

4989

AN XY:

724228

show subpopulations

Gnomad4 AFR exome

AF:

0.000150

Gnomad4 AMR exome

AF:

0.000318

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.246

Gnomad4 SAS exome

AF:

0.000222

Gnomad4 FIN exome

AF:

0.0000377

Gnomad4 NFE exome

AF:

0.0000361

Gnomad4 OTH exome

AF:

0.00586

GnomAD4 genome

AF:

0.00784

AC:

1193

AN:

152174

Hom.:

141

Cov.:

AF XY:

0.00900

AC XY:

669

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.000193

Gnomad4 AMR

AF:

0.000917

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.225

Gnomad4 SAS

AF:

0.000830

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00474

Alfa

AF:

0.00605

Hom.:

219

Bravo

AF:

0.00896

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.00104

AC:

ExAC

AF:

0.0165

AC:

2006

Asia WGS

AF:

0.0290

AC:

102

AN:

3478

ClinVar

Significance: drug response

Submissions summary: Pathogenic:1Benign:1Other:5

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

AMED syndrome, digenic

Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Alcohol dependence

Benign:1

protective, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Esophageal cancer, alcohol-related, susceptibility to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Alcohol sensitivity, acute

Other:1

drug response, no assertion criteria provided

literature only

OMIM

Feb 12, 2021

- -

Susceptibility to hangover

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

Sublingual nitroglycerin, susceptibility to poor response to

Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2010

- -

ethanol response - Toxicity

Other:1

drug response, reviewed by expert panel

curation

PharmGKB

Mar 24, 2021

PharmGKB Level of Evidence 2B: Variants in Level 2B clinical annotations are not in PharmGKB’s Tier 1 VIPs. These clinical annotations describe variant-drug combinations with a moderate level of evidence supporting the association. For example, the association may be found in multiple cohorts, but there may be a minority of studies that do not support the majority assertion. Level 2B clinical annotations must be supported by at least two independent publications. Drug-variant association: Toxicity

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.89

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Pathogenic

0.22

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.72

.;D

Eigen

Pathogenic

0.85

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

D;D

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.3

.;L

MutationTaster

Benign

1.5e-7

P;P;P;P

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-3.4

D;D

REVEL

Uncertain

0.60

Sift

Uncertain

0.0010

D;D

Sift4G

Uncertain

0.018

D;D

Polyphen

0.96

.;D

Vest4

0.48

MPC

1.0

ClinPred

0.10

GERP RS

6.0

Varity_R

0.95

gMVP

0.89

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over