NM_000690.4:c.274C>A

Variant names:

• chr12-111783212-C-A
• rs201582342
• NM_000690.4:c.274C>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000690.4(ALDH2):​c.274C>A​(p.Pro92Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000624 in 1,613,488 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P92A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.78
• Publications: 7 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013536364).
• BP6: Variant 12-111783212-C-A is Benign according to our data. Variant chr12-111783212-C-A is described in ClinVar as Benign. ClinVar VariationId is 779154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.000619 (904/1461128) while in subpopulation AMR AF = 0.0193 (863/44656). AF 95% confidence interval is 0.0183. There are 9 homozygotes in GnomAdExome4. There are 367 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 9 AR gene

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.274C>A	p.Pro92Thr	missense	Exon 3 of 13	NP_000681.2
	ALDH2	NM_001204889.2		c.219+1190C>A		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.274C>A	p.Pro92Thr	missense	Exon 3 of 13	ENSP00000261733.2	P05091-1
	ENSG00000257767	ENST00000546840.3	TSL:5	c.262C>A	p.Pro88Thr	missense	Exon 4 of 8	ENSP00000450353.4	F8VP50
	ALDH2	ENST00000871406.1		c.385C>A	p.Pro129Thr	missense	Exon 4 of 14	ENSP00000541465.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152242 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00307 AC: 768 AN: 250046 AF XY: 0.00217

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000619 AC: 904 AN: 1461128 Hom.: 9 Cov.: 31 AF XY: 0.000505 AC XY: 367 AN XY: 726804

African (AFR) AF: 0.000119 AC: 4 AN: 33478

American (AMR) AF: 0.0193 AC: 863 AN: 44656

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39682

South Asian (SAS) AF: 0.000104 AC: 9 AN: 86128

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53262

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1111660

Other (OTH) AF: 0.000348 AC: 21 AN: 60370

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152360 Hom.: 1 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74510

African (AFR) AF: 0.000144 AC: 6 AN: 41588

American (AMR) AF: 0.00608 AC: 93 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000248 Hom.: 1

Bravo AF: 0.00171

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00237 AC: 288

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.12
Eigen_PC	Benign	0.079
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	-0.14	N
PhyloP100		3.8
PrimateAI	Uncertain	0.57	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Benign	0.28
Sift	Benign	0.042	D
Sift4G	Benign	0.092	T
Polyphen		0.019	B
Vest4		0.41
MVP		0.36
MPC		0.44
ClinPred		0.059	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.72
gMVP		0.72
Mutation Taster		=82/18	polymorphism

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

Other links and lift over

dbSNP: rs201582342; hg19: chr12-112221016; COSMIC: COSV55666796;