chr12-111803962-G-A

Variant names:

• chr12-111803962-G-A
• rs671
• NM_000690.4:c.1510G>A
• ALDH2 p.Glu504Lys

GermlineCancer (beta)

Variant summary

Our verdict is Likely benign.

-4 Likely Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -4 classification points (ACMG Germline Pathogenicity v2019). BA1PS3

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 cumulative frequency of 0.00704 (AC=11,316) in the gnomAD database across 1,608,410 control chromosomes, including 1,380 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.242. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.78). Variant has been reported in ClinVar as Uncertain Significance (★★★). ClinVar reports functional evidence for this variant: "SCV006583482: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID:33355142).". This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.

• Frequency:
  • Genomes: 𝑓 0.0078 (141 hom., cov: 31)
  • Exomes 𝑓: 0.0070 (1239 hom.)
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: drug response reviewed by expert panel P:1 U:1 B:1 O:5
• Conservation: PhyloP100: 9.78
• Publications: 2 publications found

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]

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Likely_benign. The variant received -4 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); SCV006583482: Functional studies provide strong evidence of the variant having a damaging effect on the gene or gene product (PMID: 33355142).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.2420 — exceeds 5%% threshold (BA1 applied)

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_000690.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ALDH2 NM_000690.4	MANE Select	c.1510G>A p.Glu504Lys	missense	Exon 12 of 13	Prot: NP_000681.2
	ALDH2 NM_001204889.2		c.1369G>A p.Glu457Lys	missense	Exon 11 of 12	Prot: NP_001191818.1 UniProt:

ALDH2 NM_000690.4

MANE Select

HGVSc / HGVSpc.1510G>Ap.Glu504Lys

Exon rankExon 12 of 13

missense

Prot: NP_000681.2

ALDH2 NM_001204889.2

HGVSc / HGVSpc.1369G>Ap.Glu457Lys

Exon rankExon 11 of 12

missense

Prot: NP_001191818.1UniProt: P05091-2

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	ALDH2 ENST00000261733.7	TSL:1MANE Select	c.1510G>A p.Glu504Lys	missense	Exon 12 of 13	Prot: ENSP00000261733.2 UniProt:
	ALDH2 ENST00000871406.1		c.1621G>A p.Glu541Lys	missense	Exon 13 of 14	Prot: ENSP00000541465.1 UniProt:
	ALDH2 ENST00000871417.1		c.1618G>A p.Glu540Lys	missense	Exon 12 of 13	Prot: ENSP00000541476.1 UniProt:

ALDH2 ENST00000261733.7

TSL:1MANE Select

HGVSc / HGVSpc.1510G>Ap.Glu504Lys

Exon rankExon 12 of 13

missense

Prot: ENSP00000261733.2UniProt: P05091-1

ALDH2 ENST00000871406.1

HGVSc / HGVSpc.1621G>Ap.Glu541Lys

Exon rankExon 13 of 14

missense

Prot: ENSP00000541465.1UniProt: A0ACI8RCU5

ALDH2 ENST00000871417.1

HGVSc / HGVSpc.1618G>Ap.Glu540Lys

Exon rankExon 12 of 13

missense

Prot: ENSP00000541476.1UniProt: A0ACI8QM20

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00787	AC:1196	Hom:141	AN:152056	Cov:31
GnomAD2 exomes	AF: 0.0189	AC:4582	Hom:	AN:242666	Cov:
GnomAD4 exome	AF: 0.00695	AC:10123	Hom:1239	AN:1456236	Cov:30
GnomAD4 genome	AF: 0.00784	AC:1193	Hom:141	AN:152174	Cov:31
TOPMed (Bravo)	AF: 0.00896	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00543	AC:3926	Hom:432	AN:723138	Cov:
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.00512	AC:12	Hom:1	AN:2342	Cov:
ChinaMAP Phase 1	AF: 0.216	AC:	Hom:	AN:	Cov:
GenomeAsia100K	AF: 0.0290	AC:102	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.160	AC:1154	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.193	AC:23564	Hom:2332	AN:122056	Cov:
Turkish Variome	AF: 0.00119	AC:8	Hom:0	AN:6700	Cov:
UK10K	AF: 0.000529	AC:4	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.239	AC:2138	Hom:276	AN:8960	Cov:

Showing 14 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
BipEx(Bipolar disorder (including schizoaffective))	0.0000706	2	28316	0.0000348	1	28752
Epi25(Epilepsy)	0.0224	935	41758	0.00863	574	66486
SCHEMA(Schizophrenia)	0.0310	3447	111350	0.0211	3949	187600

Showing 3 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: drug response

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	1	-	ALDH2-related disorder (1)
1	-	-	AMED syndrome, digenic (1)
-	-	-	Alcohol dependence (1)
-	-	-	Alcohol sensitivity, acute (1)
-	-	-	ESOPHAGEAL CANCER, ALCOHOL-RELATED, SUSCEPTIBILITY TO (1)
-	-	-	ethanol response - Toxicity (1)
-	-	-	NITROGLYCERIN, POOR RESPONSE TO (1)
-	-	-	Susceptibility to hangover (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	28
AlphaMissense	Pathogenic	0.89
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	1.0	D
FuncVEP CTI	Pathogenic	0.73
GPN-Star LLR	N/A	-7.0
GPN-Star score	N/A	7.0
LIST_S2	Pathogenic	0.99	D
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
Mutation Taster	N/A	70/30	disease causing (ClinVar)
MutationAssessor	Benign	1.3	L
PhyloP100	Pathogenic	9.8
popEVE	Benign	-3.4
PrimateAI	Uncertain	0.69	T
PROVEAN	Uncertain	-3.4	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.018	D
Varity_R	N/A	0.95
VESM-3B	Benign	-9.5

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.020
SpliceAI score (max)	Benign	0.010	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs671;

hg19: chr12-112241766;

COSMIC: COSV55665271;

COSMIC: COSV55665271;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar