NM_000690.4:c.898+52G>C

Variant names:

• chr12-111792215-G-C
• rs4646776
• NM_000690.4:c.898+52G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000690.4(ALDH2):​c.898+52G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00805 in 1,367,344 control chromosomes in the GnomAD database, including 1,354 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 0.0079 (143 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (1211 hom.)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.22
• Publications: 20 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000690.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	NM_000690.4	MANE Select	c.898+52G>C		intron	N/A	NP_000681.2
	ALDH2	NM_001204889.2		c.757+52G>C		intron	N/A	NP_001191818.1	P05091-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	ENST00000261733.7	TSL:1 MANE Select	c.898+52G>C		intron	N/A	ENSP00000261733.2	P05091-1
	ALDH2	ENST00000871406.1		c.1009+52G>C		intron	N/A	ENSP00000541465.1
	ALDH2	ENST00000871417.1		c.898+52G>C		intron	N/A	ENSP00000541476.1

Frequencies

GnomAD3 genomes AF: 0.00790 AC: 1203 AN: 152190 Hom.: 143 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.226

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.0191 AC: 4015 AN: 210124 AF XY: 0.0175

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000471

Gnomad ASJ exome AF: 0.000382

Gnomad EAS exome AF: 0.253

Gnomad FIN exome AF: 0.0000495

Gnomad NFE exome AF: 0.0000201

Gnomad OTH exome AF: 0.00623

GnomAD4 exome AF: 0.00807 AC: 9806 AN: 1215036 Hom.: 1211 Cov.: 17 AF XY: 0.00794 AC XY: 4879 AN XY: 614366

African (AFR) AF: 0.0000375 AC: 1 AN: 26684

American (AMR) AF: 0.000407 AC: 13 AN: 31980

Ashkenazi Jewish (ASJ) AF: 0.000349 AC: 8 AN: 22930

East Asian (EAS) AF: 0.246 AC: 9425 AN: 38372

South Asian (SAS) AF: 0.000236 AC: 18 AN: 76394

European-Finnish (FIN) AF: 0.0000387 AC: 2 AN: 51702

Middle Eastern (MID) AF: 0.000194 AC: 1 AN: 5160

European-Non Finnish (NFE) AF: 0.0000385 AC: 35 AN: 910016

Other (OTH) AF: 0.00585 AC: 303 AN: 51798

GnomAD4 genome AF: 0.00788 AC: 1200 AN: 152308 Hom.: 143 Cov.: 32 AF XY: 0.00911 AC XY: 678 AN XY: 74458

African (AFR) AF: 0.00 AC: 0 AN: 41584

American (AMR) AF: 0.000850 AC: 13 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.226 AC: 1170 AN: 5168

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68020

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00214 Hom.: 3

Bravo AF: 0.00895

Asia WGS AF: 0.0300 AC: 103 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.48
DANN	Benign	0.54
PhyloP100		-1.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs4646776; hg19: chr12-112230019; COSMIC: COSV55667649; COSMIC: COSV55667649;