12-111790910-T-C

Variant names:

• chr12-111790910-T-C
• rs440
• NM_000690.4:c.681+348T>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.681+348T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 151,950 control chromosomes in the GnomAD database, including 2,432 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 (2432 hom., cov: 32)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.693
• Publications: 10 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]

ENSG00000257767 (HGNC:):

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 = 0.224 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.681+348T>C		intron_variant	Intron 6 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.540+348T>C		intron_variant	Intron 5 of 11		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.681+348T>C		intron_variant	Intron 6 of 12	1	NM_000690.4	ENSP00000261733.2
ENSG00000257767	ENST00000546840.3	c.669+348T>C		intron_variant	Intron 7 of 7	5		ENSP00000450353.4
ALDH2	ENST00000416293.7	c.540+348T>C		intron_variant	Intron 5 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.*557+348T>C		intron_variant	Intron 7 of 13	3		ENSP00000448179.1

Frequencies

GnomAD3 genomes AF: 0.176 AC: 26747 AN: 151832 Hom.: 2434 Cov.: 32

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.0912

Gnomad EAS AF: 0.235

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.277

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.186

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

GnomAD4 genome AF: 0.176 AC: 26743 AN: 151950 Hom.: 2432 Cov.: 32 AF XY: 0.175 AC XY: 12983 AN XY: 74274

African (AFR) AF: 0.191 AC: 7900 AN: 41458

American (AMR) AF: 0.173 AC: 2638 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.0912 AC: 316 AN: 3464

East Asian (EAS) AF: 0.235 AC: 1215 AN: 5162

South Asian (SAS) AF: 0.212 AC: 1017 AN: 4806

European-Finnish (FIN) AF: 0.152 AC: 1603 AN: 10554

Middle Eastern (MID) AF: 0.272 AC: 79 AN: 290

European-Non Finnish (NFE) AF: 0.169 AC: 11457 AN: 67932

Other (OTH) AF: 0.182 AC: 385 AN: 2110

Alfa AF: 0.179 Hom.: 292

Bravo AF: 0.179

Asia WGS AF: 0.246 AC: 855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	6.9
DANN	Benign	0.86
PhyloP100		0.69
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: rs440; hg19: chr12-112228714;