12-111782000-G-C

Position:

• chr12-111782000-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The ENST00000261733.7(ALDH2):​c.197G>C​(p.Cys66Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH2 ENST00000261733.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.69

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.197G>C	p.Cys66Ser	missense_variant	2/13	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.197G>C	p.Cys66Ser	missense_variant	2/12		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.197G>C	p.Cys66Ser	missense_variant	2/13	1	NM_000690.4	ENSP00000261733	P1
ALDH2	ENST00000416293.7	c.197G>C	p.Cys66Ser	missense_variant	2/12	2		ENSP00000403349
ALDH2	ENST00000548536.1	c.*73G>C		3_prime_UTR_variant, NMD_transcript_variant	3/14	3		ENSP00000448179

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 29, 2023

The c.197G>C (p.C66S) alteration is located in exon 2 (coding exon 2) of the ALDH2 gene. This alteration results from a G to C substitution at nucleotide position 197, causing the cysteine (C) at amino acid position 66 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	28
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.72	.;.;D
Eigen	Benign	0.052
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;T
M_CAP	Benign	0.035	D
MetaRNN	Uncertain	0.73	D;D;D
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.78	.;N;N
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.7	.;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.030	.;D;D
Sift4G	Uncertain	0.027	D;D;D
Polyphen		0.081	.;.;B
Vest4		0.85, 0.87
MutPred		0.63		.;Gain of disorder (P = 0.0017);Gain of disorder (P = 0.0017);
MVP		0.42
MPC		0.42
ClinPred		0.99	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.89
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112219804;