12-111796564-T-C

Variant names:

• chr12-111796564-T-C
• rs968529
• NM_000690.4:c.1084-1514T>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.1084-1514T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.95 in 152,144 control chromosomes in the GnomAD database, including 68,663 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 0.95 (68663 hom., cov: 29)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.74
• Publications: 12 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=-1.04).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.98 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.1084-1514T>C		intron	N/A	NP_000681.2
	ALDH2	NM_001204889.2		c.943-1514T>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.1084-1514T>C		intron	N/A	ENSP00000261733.2	P05091-1
	ALDH2	ENST00000871406.1		c.1195-1514T>C		intron	N/A	ENSP00000541465.1
	ALDH2	ENST00000871417.1		c.1192-1514T>C		intron	N/A	ENSP00000541476.1

Frequencies

GnomAD3 genomes AF: 0.949 AC: 144343 AN: 152026 Hom.: 68603 Cov.: 29

Gnomad AFR AF: 0.988

Gnomad AMI AF: 0.896

Gnomad AMR AF: 0.949

Gnomad ASJ AF: 0.926

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.959

Gnomad FIN AF: 0.918

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.929

Gnomad OTH AF: 0.943

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

GnomAD4 genome AF: 0.950 AC: 144463 AN: 152144 Hom.: 68663 Cov.: 29 AF XY: 0.949 AC XY: 70601 AN XY: 74378

African (AFR) AF: 0.988 AC: 41002 AN: 41504

American (AMR) AF: 0.949 AC: 14473 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.926 AC: 3211 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5180 AN: 5182

South Asian (SAS) AF: 0.960 AC: 4627 AN: 4822

European-Finnish (FIN) AF: 0.918 AC: 9717 AN: 10588

Middle Eastern (MID) AF: 0.959 AC: 282 AN: 294

European-Non Finnish (NFE) AF: 0.929 AC: 63161 AN: 68014

Other (OTH) AF: 0.944 AC: 1993 AN: 2112

Alfa AF: 0.935 Hom.: 110636

Bravo AF: 0.955

Asia WGS AF: 0.980 AC: 3407 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.057
DANN	Benign	0.27
PhyloP100		-3.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs968529; hg19: chr12-112234368;