NM_000690.4:c.1521+428G>A

Variant names:

• chr12-111804401-G-A
• rs2158029
• NM_000690.4:c.1521+428G>A

Variant summary

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

The NM_000690.4(ALDH2):​c.1521+428G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0706 in 152,236 control chromosomes in the GnomAD database, including 1,475 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 0.071 (1475 hom., cov: 31)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.840
• Publications: 5 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=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.594 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.1521+428G>A		intron_variant	Intron 12 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.1380+428G>A		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.1521+428G>A		intron_variant	Intron 12 of 12	1	NM_000690.4	ENSP00000261733.2
ALDH2	ENST00000416293.7	c.1380+428G>A		intron_variant	Intron 11 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.*1397+428G>A		intron_variant	Intron 13 of 13	3		ENSP00000448179.1
ALDH2	ENST00000549106.1	n.*100+428G>A		intron_variant	Intron 3 of 3	3		ENSP00000474669.1

Frequencies

GnomAD3 genomes AF: 0.0705 AC: 10721 AN: 152118 Hom.: 1478 Cov.: 31

Gnomad AFR AF: 0.106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.147

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.612

Gnomad SAS AF: 0.0960

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0538

Gnomad NFE AF: 0.00344

Gnomad OTH AF: 0.0712

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

GnomAD4 genome AF: 0.0706 AC: 10744 AN: 152236 Hom.: 1475 Cov.: 31 AF XY: 0.0771 AC XY: 5738 AN XY: 74434

African (AFR) AF: 0.107 AC: 4426 AN: 41534

American (AMR) AF: 0.148 AC: 2253 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.612 AC: 3154 AN: 5154

South Asian (SAS) AF: 0.0967 AC: 467 AN: 4830

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10628

Middle Eastern (MID) AF: 0.0578 AC: 17 AN: 294

European-Non Finnish (NFE) AF: 0.00344 AC: 234 AN: 68032

Other (OTH) AF: 0.0719 AC: 152 AN: 2114

Alfa AF: 0.0327 Hom.: 54

Bravo AF: 0.0871

Asia WGS AF: 0.251 AC: 872 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.41
DANN	Benign	0.89
PhyloP100		-0.84
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: rs2158029; hg19: chr12-112242205;