NM_000690.4:c.1522-2177A>C

Variant names:

• chr12-111807366-A-C
• rs11066028
• NM_000690.4:c.1522-2177A>C

Variant summary

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

The NM_000690.4(ALDH2):​c.1522-2177A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,838 control chromosomes in the GnomAD database, including 19,853 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 0.45 (19853 hom., cov: 31)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36
• Publications: 24 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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	NM_000690.4	MANE Select	c.1522-2177A>C		intron	N/A	NP_000681.2
	ALDH2	NM_001204889.2		c.1381-2177A>C		intron	N/A	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.1522-2177A>C		intron	N/A	ENSP00000261733.2	P05091-1
	ALDH2	ENST00000871406.1		c.1633-2177A>C		intron	N/A	ENSP00000541465.1
	ALDH2	ENST00000871417.1		c.1630-2177A>C		intron	N/A	ENSP00000541476.1

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68606 AN: 151722 Hom.: 19799 Cov.: 31

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.434

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.453 AC: 68725 AN: 151838 Hom.: 19853 Cov.: 31 AF XY: 0.457 AC XY: 33896 AN XY: 74198

African (AFR) AF: 0.770 AC: 31901 AN: 41448

American (AMR) AF: 0.434 AC: 6614 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.157 AC: 543 AN: 3466

East Asian (EAS) AF: 0.902 AC: 4664 AN: 5172

South Asian (SAS) AF: 0.589 AC: 2838 AN: 4816

European-Finnish (FIN) AF: 0.232 AC: 2426 AN: 10462

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.272 AC: 18465 AN: 67926

Other (OTH) AF: 0.432 AC: 912 AN: 2110

Alfa AF: 0.339 Hom.: 33256

Bravo AF: 0.482

Asia WGS AF: 0.708 AC: 2460 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.62
PhyloP100		-1.4
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: rs11066028; hg19: chr12-112245170;