12-111807833-T-G

Variant names:

• chr12-111807833-T-G
• rs16941669
• NM_000690.4:c.1522-1710T>G

Variant summary

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

The NM_000690.4(ALDH2):​c.1522-1710T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 151,812 control chromosomes in the GnomAD database, including 914 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 0.10 (914 hom., cov: 31)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.428
• Publications: 28 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=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.1522-1710T>G		intron_variant	Intron 12 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.1381-1710T>G		intron_variant	Intron 11 of 11		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.1522-1710T>G		intron_variant	Intron 12 of 12	1	NM_000690.4	ENSP00000261733.2
ALDH2	ENST00000416293.7	c.1381-1710T>G		intron_variant	Intron 11 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.*1398-1710T>G		intron_variant	Intron 13 of 13	3		ENSP00000448179.1
ALDH2	ENST00000549106.1	n.*101-1710T>G		intron_variant	Intron 3 of 3	3		ENSP00000474669.1

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15225 AN: 151708 Hom.: 914 Cov.: 31

Gnomad AFR AF: 0.0916

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.103

Gnomad ASJ AF: 0.0559

Gnomad EAS AF: 0.0547

Gnomad SAS AF: 0.295

Gnomad FIN AF: 0.0778

Gnomad MID AF: 0.0828

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0987

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

GnomAD4 genome AF: 0.100 AC: 15242 AN: 151812 Hom.: 914 Cov.: 31 AF XY: 0.104 AC XY: 7740 AN XY: 74136

African (AFR) AF: 0.0916 AC: 3793 AN: 41412

American (AMR) AF: 0.103 AC: 1564 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0559 AC: 194 AN: 3472

East Asian (EAS) AF: 0.0550 AC: 283 AN: 5144

South Asian (SAS) AF: 0.296 AC: 1418 AN: 4796

European-Finnish (FIN) AF: 0.0778 AC: 816 AN: 10494

Middle Eastern (MID) AF: 0.0822 AC: 24 AN: 292

European-Non Finnish (NFE) AF: 0.101 AC: 6835 AN: 67964

Other (OTH) AF: 0.101 AC: 212 AN: 2108

Alfa AF: 0.0983 Hom.: 1451

Bravo AF: 0.0955

Asia WGS AF: 0.187 AC: 651 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	7.6
DANN	Benign	0.75
PhyloP100		0.43
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: rs16941669; hg19: chr12-112245637;