NM_000690.4:c.1521+2636C>T

Variant names:

• chr12-111806609-C-T
• rs16941667
• NM_000690.4:c.1521+2636C>T

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+2636C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0844 in 152,208 control chromosomes in the GnomAD database, including 639 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 0.084 (639 hom., cov: 32)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.718
• Publications: 23 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.123 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.1521+2636C>T		intron_variant	Intron 12 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.1380+2636C>T		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+2636C>T		intron_variant	Intron 12 of 12	1	NM_000690.4	ENSP00000261733.2
ALDH2	ENST00000416293.7	c.1380+2636C>T		intron_variant	Intron 11 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.*1397+2636C>T		intron_variant	Intron 13 of 13	3		ENSP00000448179.1
ALDH2	ENST00000549106.1	n.*100+2636C>T		intron_variant	Intron 3 of 3	3		ENSP00000474669.1

Frequencies

GnomAD3 genomes AF: 0.0844 AC: 12833 AN: 152090 Hom.: 638 Cov.: 32

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.123

Gnomad AMR AF: 0.0795

Gnomad ASJ AF: 0.0412

Gnomad EAS AF: 0.00231

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0400

Gnomad MID AF: 0.165

Gnomad NFE AF: 0.0773

Gnomad OTH AF: 0.104

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

GnomAD4 genome AF: 0.0844 AC: 12845 AN: 152208 Hom.: 639 Cov.: 32 AF XY: 0.0814 AC XY: 6060 AN XY: 74424

African (AFR) AF: 0.126 AC: 5225 AN: 41514

American (AMR) AF: 0.0794 AC: 1214 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 143 AN: 3470

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5176

South Asian (SAS) AF: 0.0409 AC: 197 AN: 4820

European-Finnish (FIN) AF: 0.0400 AC: 424 AN: 10610

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5254 AN: 68014

Other (OTH) AF: 0.102 AC: 215 AN: 2112

Alfa AF: 0.0846 Hom.: 769

Bravo AF: 0.0903

Asia WGS AF: 0.0270 AC: 97 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	5.2
DANN	Benign	0.75
PhyloP100		-0.72
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: rs16941667; hg19: chr12-112244413;