rs4648328

Positions:

• chr12-111784984-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000690.4(ALDH2):​c.361-283C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 152,134 control chromosomes in the GnomAD database, including 2,478 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 (2478 hom., cov: 32)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.812

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.222 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.361-283C>T		intron_variant		ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.220-283C>T		intron_variant			NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.361-283C>T		intron_variant		1	NM_000690.4	ENSP00000261733.2
ENSG00000257767	ENST00000546840.3	c.349-283C>T		intron_variant		5		ENSP00000450353.4
ALDH2	ENST00000416293.7	c.220-283C>T		intron_variant		2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.*237-283C>T		intron_variant		3		ENSP00000448179.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26935 AN: 152016 Hom.: 2480 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0908

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.211

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.259

Gnomad NFE AF: 0.167

Gnomad OTH AF: 0.187

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

GnomAD4 genome AF: 0.177 AC: 26931 AN: 152134 Hom.: 2478 Cov.: 32 AF XY: 0.176 AC XY: 13074 AN XY: 74388

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.172

Gnomad4 ASJ AF: 0.0908

Gnomad4 EAS AF: 0.233

Gnomad4 SAS AF: 0.210

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.167

Gnomad4 OTH AF: 0.183

Alfa AF: 0.170 Hom.: 2254

Bravo AF: 0.181

Asia WGS AF: 0.245 AC: 850 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	5.1
DANN	Benign	0.71

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

Publications

LitVar

Other links and lift over

dbSNP: rs4648328; hg19: chr12-112222788;