12-111795214-T-C

Variant names:

• chr12-111795214-T-C
• rs10744777
• NM_000690.4:c.1083+2432T>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.1083+2432T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 152,116 control chromosomes in the GnomAD database, including 26,091 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 0.53 (26091 hom., cov: 32)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.495
• Publications: 57 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.922 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.1083+2432T>C		intron	N/A	NP_000681.2
	ALDH2	NM_001204889.2		c.942+2432T>C		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.1083+2432T>C		intron	N/A	ENSP00000261733.2
	ALDH2	ENST00000416293.7	TSL:2	c.942+2432T>C		intron	N/A	ENSP00000403349.3
	ALDH2	ENST00000548536.1	TSL:3	n.*959+2432T>C		intron	N/A	ENSP00000448179.1

Frequencies

GnomAD3 genomes AF: 0.526 AC: 79925 AN: 151998 Hom.: 26039 Cov.: 32

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.416

Gnomad AMR AF: 0.474

Gnomad ASJ AF: 0.198

Gnomad EAS AF: 0.944

Gnomad SAS AF: 0.703

Gnomad FIN AF: 0.342

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.325

Gnomad OTH AF: 0.484

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

GnomAD4 genome AF: 0.526 AC: 80038 AN: 152116 Hom.: 26091 Cov.: 32 AF XY: 0.533 AC XY: 39634 AN XY: 74376

African (AFR) AF: 0.882 AC: 36588 AN: 41494

American (AMR) AF: 0.474 AC: 7245 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.198 AC: 686 AN: 3466

East Asian (EAS) AF: 0.944 AC: 4889 AN: 5178

South Asian (SAS) AF: 0.702 AC: 3394 AN: 4832

European-Finnish (FIN) AF: 0.342 AC: 3618 AN: 10584

Middle Eastern (MID) AF: 0.520 AC: 153 AN: 294

European-Non Finnish (NFE) AF: 0.325 AC: 22070 AN: 67980

Other (OTH) AF: 0.482 AC: 1016 AN: 2106

Alfa AF: 0.370 Hom.: 14365

Bravo AF: 0.550

Asia WGS AF: 0.768 AC: 2671 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	1.7
DANN	Benign	0.36
PhyloP100		-0.49
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: rs10744777; hg19: chr12-112233018;