12-111797979-C-G

Variant names:

• chr12-111797979-C-G
• rs4646778
• NM_000690.4:c.1084-99C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_000690.4(ALDH2):​c.1084-99C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000782 in 1,278,112 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.8e-7 (0 hom.)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.1084-99C>G		intron_variant	Intron 9 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.943-99C>G		intron_variant	Intron 8 of 11		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.1084-99C>G		intron_variant	Intron 9 of 12	1	NM_000690.4	ENSP00000261733.2
ALDH2	ENST00000416293.7	c.943-99C>G		intron_variant	Intron 8 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.*960-99C>G		intron_variant	Intron 10 of 13	3		ENSP00000448179.1
ALDH2	ENST00000549106.1	n.172-99C>G		intron_variant	Intron 1 of 3	3		ENSP00000474669.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.82e-7 AC: 1 AN: 1278112 Hom.: 0 AF XY: 0.00000156 AC XY: 1 AN XY: 640470

African (AFR) AF: 0.00 AC: 0 AN: 29704

American (AMR) AF: 0.00 AC: 0 AN: 37896

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24296

East Asian (EAS) AF: 0.00 AC: 0 AN: 37762

South Asian (SAS) AF: 0.00 AC: 0 AN: 78380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48200

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5322

European-Non Finnish (NFE) AF: 0.00000104 AC: 1 AN: 962258

Other (OTH) AF: 0.00 AC: 0 AN: 54294

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	4.3
DANN	Benign	0.49
PhyloP100		-0.11

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: rs4646778; hg19: chr12-112235783;