rs4646778

Positions:

• chr12-111797979-C-A

Variant summary

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

The NM_000690.4(ALDH2):​c.1084-99C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,428,688 control chromosomes in the GnomAD database, including 22,423 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 (2494 hom., cov: 32)
  • Exomes 𝑓: 0.17 (19929 hom.)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108

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

Verdict is Benign. Variant got -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 = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.1084-99C>A		intron_variant		ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.943-99C>A		intron_variant			NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.1084-99C>A		intron_variant		1	NM_000690.4	ENSP00000261733	P1
ALDH2	ENST00000416293.7	c.943-99C>A		intron_variant		2		ENSP00000403349
ALDH2	ENST00000548536.1	c.*960-99C>A		intron_variant, NMD_transcript_variant		3		ENSP00000448179
ALDH2	ENST00000549106.1	c.173-99C>A		intron_variant, NMD_transcript_variant		3		ENSP00000474669

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27085 AN: 151972 Hom.: 2496 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.175 AC: 222800 AN: 1276598 Hom.: 19929 AF XY: 0.174 AC XY: 111600 AN XY: 639758

Gnomad4 AFR exome AF: 0.197

Gnomad4 AMR exome AF: 0.170

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.185

Gnomad4 SAS exome AF: 0.213

Gnomad4 FIN exome AF: 0.155

Gnomad4 NFE exome AF: 0.173

Gnomad4 OTH exome AF: 0.176

GnomAD4 genome AF: 0.178 AC: 27081 AN: 152090 Hom.: 2494 Cov.: 32 AF XY: 0.177 AC XY: 13135 AN XY: 74342

Gnomad4 AFR AF: 0.199

Gnomad4 AMR AF: 0.173

Gnomad4 ASJ AF: 0.0911

Gnomad4 EAS AF: 0.234

Gnomad4 SAS AF: 0.211

Gnomad4 FIN AF: 0.152

Gnomad4 NFE AF: 0.168

Gnomad4 OTH AF: 0.186

Alfa AF: 0.173 Hom.: 2915

Bravo AF: 0.182

Asia WGS AF: 0.248 AC: 863 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	4.1
DANN	Benign	0.57

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: rs4646778; hg19: chr12-112235783; COSMIC: COSV55671112; COSMIC: COSV55671112;