12-111771537-C-T

Variant names:

• chr12-111771537-C-T
• rs4767944
• NM_000690.4:c.114+4441C>T

Variant summary

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

The NM_000690.4(ALDH2):​c.114+4441C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0516 in 152,262 control chromosomes in the GnomAD database, including 1,216 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 0.052 (1216 hom., cov: 32)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.845
• Publications: 16 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]

ENSG00000257767 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.599 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.114+4441C>T		intron_variant	Intron 1 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.114+4441C>T		intron_variant	Intron 1 of 11		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.114+4441C>T		intron_variant	Intron 1 of 12	1	NM_000690.4	ENSP00000261733.2
ENSG00000257767	ENST00000546840.3	c.103-10381C>T		intron_variant	Intron 2 of 7	5		ENSP00000450353.4
ALDH2	ENST00000416293.7	c.114+4441C>T		intron_variant	Intron 1 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.115-4068C>T		intron_variant	Intron 1 of 13	3		ENSP00000448179.1

Frequencies

GnomAD3 genomes AF: 0.0516 AC: 7848 AN: 152144 Hom.: 1221 Cov.: 32

Gnomad AFR AF: 0.0526

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.105

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.617

Gnomad SAS AF: 0.0987

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.00315

Gnomad OTH AF: 0.0593

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

GnomAD4 genome AF: 0.0516 AC: 7853 AN: 152262 Hom.: 1216 Cov.: 32 AF XY: 0.0575 AC XY: 4282 AN XY: 74458

African (AFR) AF: 0.0525 AC: 2180 AN: 41552

American (AMR) AF: 0.105 AC: 1606 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3468

East Asian (EAS) AF: 0.617 AC: 3191 AN: 5172

South Asian (SAS) AF: 0.0996 AC: 481 AN: 4828

European-Finnish (FIN) AF: 0.00207 AC: 22 AN: 10618

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.00315 AC: 214 AN: 68020

Other (OTH) AF: 0.0591 AC: 125 AN: 2114

Alfa AF: 0.0232 Hom.: 672

Bravo AF: 0.0640

Asia WGS AF: 0.248 AC: 861 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	2.3
DANN	Benign	0.27
PhyloP100		0.84
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: rs4767944; hg19: chr12-112209341;