12-111807366-A-C

Position:

• chr12-111807366-A-C

Variant summary

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

The NM_000690.4(ALDH2):​c.1522-2177A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.453 in 151,838 control chromosomes in the GnomAD database, including 19,853 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 0.45 (19853 hom., cov: 31)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.36

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=-0.97).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.88 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.1522-2177A>C		intron_variant		ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.1381-2177A>C		intron_variant			NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.1522-2177A>C		intron_variant		1	NM_000690.4	ENSP00000261733	P1
ALDH2	ENST00000416293.7	c.1381-2177A>C		intron_variant		2		ENSP00000403349
ALDH2	ENST00000548536.1	c.*1398-2177A>C		intron_variant, NMD_transcript_variant		3		ENSP00000448179
ALDH2	ENST00000549106.1	c.*101-2177A>C		intron_variant, NMD_transcript_variant		3		ENSP00000474669

Frequencies

GnomAD3 genomes AF: 0.452 AC: 68606 AN: 151722 Hom.: 19799 Cov.: 31

Gnomad AFR AF: 0.769

Gnomad AMI AF: 0.259

Gnomad AMR AF: 0.434

Gnomad ASJ AF: 0.157

Gnomad EAS AF: 0.902

Gnomad SAS AF: 0.589

Gnomad FIN AF: 0.232

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.272

Gnomad OTH AF: 0.434

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

GnomAD4 genome AF: 0.453 AC: 68725 AN: 151838 Hom.: 19853 Cov.: 31 AF XY: 0.457 AC XY: 33896 AN XY: 74198

Gnomad4 AFR AF: 0.770

Gnomad4 AMR AF: 0.434

Gnomad4 ASJ AF: 0.157

Gnomad4 EAS AF: 0.902

Gnomad4 SAS AF: 0.589

Gnomad4 FIN AF: 0.232

Gnomad4 NFE AF: 0.272

Gnomad4 OTH AF: 0.432

Alfa AF: 0.307 Hom.: 16192

Bravo AF: 0.482

Asia WGS AF: 0.708 AC: 2460 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	2.0
DANN	Benign	0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs11066028; hg19: chr12-112245170;