12-111782020-A-C

Variant names:

• chr12-111782020-A-C
• NM_000690.4:c.217A>C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_000690.4(ALDH2):​c.217A>C​(p.Lys73Gln) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ALDH2 NM_000690.4 missense, splice_region
• Scores: Splicing: ADA: 0.5613
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.63

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a modified_residue N6-acetyllysine (size 0) in uniprot entity ALDH2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26274288).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.217A>C	p.Lys73Gln	missense_variant, splice_region_variant	Exon 2 of 13	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.217A>C	p.Lys73Gln	missense_variant, splice_region_variant	Exon 2 of 12		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.217A>C	p.Lys73Gln	missense_variant, splice_region_variant	Exon 2 of 13	1	NM_000690.4	ENSP00000261733.2
ENSG00000257767	ENST00000546840.3	c.205A>C	p.Lys69Gln	missense_variant, splice_region_variant	Exon 3 of 8	5		ENSP00000450353.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.64	.;.;D
Eigen	Benign	0.0061
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Benign	0.038	D
MetaRNN	Benign	0.25	T;T;T
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.49	.;N;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.7	.;D;D
REVEL	Benign	0.068
Sift	Uncertain	0.015	.;D;D
Sift4G	Benign	0.16	T;D;T
Polyphen		0.0070	.;.;B
Vest4		0.56, 0.44
MutPred		0.42		.;Loss of ubiquitination at K73 (P = 0.0183);Loss of ubiquitination at K73 (P = 0.0183);
MVP		0.49
MPC		0.33
ClinPred		0.96	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.56
dbscSNV1_RF	Benign	0.53
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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112219824;