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GeneBe

rs671

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

7
5
4

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]

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 UniProt
ALDH2NM_000690.4 linkuse as main transcriptc.1510G>A p.Glu504Lys missense_variant 12/13 ENST00000261733.7
ALDH2NM_001204889.2 linkuse as main transcriptc.1369G>A p.Glu457Lys missense_variant 11/12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
ALDH2ENST00000261733.7 linkuse as main transcriptc.1510G>A p.Glu504Lys missense_variant 12/131 NM_000690.4 P1P05091-1
ALDH2ENST00000416293.7 linkuse as main transcriptc.1369G>A p.Glu457Lys missense_variant 11/122 P05091-2
ALDH2ENST00000548536.1 linkuse as main transcriptc.*1386G>A 3_prime_UTR_variant, NMD_transcript_variant 13/143
ALDH2ENST00000549106.1 linkuse as main transcriptc.*89G>A 3_prime_UTR_variant, NMD_transcript_variant 3/43

Frequencies

GnomAD3 genomes
AF:
0.00787
AC:
1196
AN:
152056
Hom.:
141
Cov.:
31
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.:
30
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.:
31
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:
0
ALSPAC
AF:
0.00104
AC:
4
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 providedliterature onlyOMIMFeb 01, 2010- -
Alcohol dependence Benign:1
protective, no assertion criteria providedliterature onlyOMIMFeb 01, 2010- -
Esophageal cancer, alcohol-related, susceptibility to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMFeb 01, 2010- -
Susceptibility to hangover Other:1
risk factor, no assertion criteria providedliterature onlyOMIMFeb 01, 2010- -
Alcohol sensitivity, acute Other:1
drug response, no assertion criteria providedliterature onlyOMIMFeb 12, 2021- -
Sublingual nitroglycerin, susceptibility to poor response to Other:1
risk factor, no assertion criteria providedliterature onlyOMIMFeb 01, 2010- -
ethanol response - Toxicity Other:1
drug response, reviewed by expert panelcurationPharmGKBMar 24, 2021PharmGKB 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
T
BayesDel_noAF
Pathogenic
0.22
Cadd
Pathogenic
31
Dann
Pathogenic
1.0
Eigen
Pathogenic
0.85
Eigen_PC
Pathogenic
0.87
FATHMM_MKL
Pathogenic
1.0
D
LIST_S2
Pathogenic
0.99
D;D
MetaRNN
Benign
0.0019
T;T
MetaSVM
Benign
-1.1
T
MutationTaster
Benign
1.5e-7
P;P;P;P
PrimateAI
Uncertain
0.69
T
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
T
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.

Other links and lift over

dbSNP: rs671; hg19: chr12-112241766; COSMIC: COSV55665271; COSMIC: COSV55665271; API