rs671

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: 1234 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

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

• PS3: 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).
• BA1: 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	NP_000681.2
	ALDH2	NM_001204889.2		c.1369G>A	p.Glu457Lys	missense	Exon 11 of 12	NP_001191818.1	P05091-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	ENST00000261733.7	TSL:1 MANE Select	c.1510G>A	p.Glu504Lys	missense	Exon 12 of 13	ENSP00000261733.2	P05091-1
	ALDH2	ENST00000871406.1		c.1621G>A	p.Glu541Lys	missense	Exon 13 of 14	ENSP00000541465.1	A0ACI8RCU5
	ALDH2	ENST00000871417.1		c.1618G>A	p.Glu540Lys	missense	Exon 12 of 13	ENSP00000541476.1	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	0.00787	1196	141	152056	31
GnomAD2 exomes	0.0189	4582		242666
GnomAD4 exome	0.00695	10123	1239	1456236	30
GnomAD4 genome	0.00784	1193	141	152174	31
TOPMed (Bravo)	0.00896
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	0.00543	3926	432	723138
Local & regional cohorts 8 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	0.00512	12	1	2342
ChinaMAP Phase 1	0.216
GenomeAsia100K	0.0290	102		3478
Korea4K (4,157 Koreans)	0.160	1154		7234
ToMMo 61KJPN (+60KJPN MNV)	0.193	23564	2332	122056
Turkish Variome	0.00119	8	0	6700
UK10K	0.000529	4		7562
WBBC (Westlake BioBank for Chinese) pilot	0.239	2138	276	8960

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

Showing 27 of 27 scores

Splicing Scores

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

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.

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