12-111792232-G-A

Variant names:

• chr12-111792232-G-A
• rs4646777
• NM_000690.4:c.898+69G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000690.4(ALDH2):​c.898+69G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.172 in 1,229,896 control chromosomes in the GnomAD database, including 18,762 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2414 hom., cov: 32)
  • Exomes 𝑓: 0.17 (16348 hom.)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.10
• Publications: 26 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Variant Effect in Transcripts

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

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	NM_000690.4	MANE Select	c.898+69G>A		intron	N/A	NP_000681.2
	ALDH2	NM_001204889.2		c.757+69G>A		intron	N/A	NP_001191818.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	ENST00000261733.7	TSL:1 MANE Select	c.898+69G>A		intron	N/A	ENSP00000261733.2
	ALDH2	ENST00000416293.7	TSL:2	c.757+69G>A		intron	N/A	ENSP00000403349.3
	ALDH2	ENST00000548536.1	TSL:3	n.*774+69G>A		intron	N/A	ENSP00000448179.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26731 AN: 152140 Hom.: 2416 Cov.: 32

Gnomad AFR AF: 0.190

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.268

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.186

GnomAD4 exome AF: 0.171 AC: 184310 AN: 1077638 Hom.: 16348 AF XY: 0.172 AC XY: 94278 AN XY: 549602

African (AFR) AF: 0.188 AC: 4512 AN: 23954

American (AMR) AF: 0.169 AC: 4971 AN: 29426

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2130 AN: 21238

East Asian (EAS) AF: 0.184 AC: 6939 AN: 37662

South Asian (SAS) AF: 0.212 AC: 15275 AN: 71894

European-Finnish (FIN) AF: 0.154 AC: 7894 AN: 51296

Middle Eastern (MID) AF: 0.250 AC: 1182 AN: 4730

European-Non Finnish (NFE) AF: 0.169 AC: 133258 AN: 790232

Other (OTH) AF: 0.173 AC: 8149 AN: 47206

GnomAD4 genome AF: 0.176 AC: 26727 AN: 152258 Hom.: 2414 Cov.: 32 AF XY: 0.174 AC XY: 12982 AN XY: 74442

African (AFR) AF: 0.190 AC: 7898 AN: 41558

American (AMR) AF: 0.172 AC: 2632 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0911 AC: 316 AN: 3468

East Asian (EAS) AF: 0.233 AC: 1208 AN: 5174

South Asian (SAS) AF: 0.211 AC: 1018 AN: 4830

European-Finnish (FIN) AF: 0.152 AC: 1610 AN: 10616

Middle Eastern (MID) AF: 0.260 AC: 76 AN: 292

European-Non Finnish (NFE) AF: 0.168 AC: 11449 AN: 67998

Other (OTH) AF: 0.183 AC: 387 AN: 2114

Alfa AF: 0.174 Hom.: 1743

Bravo AF: 0.179

Asia WGS AF: 0.245 AC: 850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.016
DANN	Benign	0.64
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4646777; hg19: chr12-112230036; COSMIC: COSV55671103; COSMIC: COSV55671103;