12-111782020-A-G

Position:

• chr12-111782020-A-G

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>G​(p.Lys73Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000685 in 1,460,556 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: ALDH2 NM_000690.4 missense, splice_region
• Scores: Splicing: ADA: 0.1328
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• 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]

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=0.17434895).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.217A>G	p.Lys73Glu	missense_variant, splice_region_variant	2/13	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.217A>G	p.Lys73Glu	missense_variant, splice_region_variant	2/12		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.217A>G	p.Lys73Glu	missense_variant, splice_region_variant	2/13	1	NM_000690.4	ENSP00000261733	P1
ALDH2	ENST00000416293.7	c.217A>G	p.Lys73Glu	missense_variant, splice_region_variant	2/12	2		ENSP00000403349
ALDH2	ENST00000548536.1	c.*93A>G		splice_region_variant, 3_prime_UTR_variant, NMD_transcript_variant	3/14	3		ENSP00000448179

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000685 AC: 10 AN: 1460556 Hom.: 0 Cov.: 30 AF XY: 0.00000826 AC XY: 6 AN XY: 726632

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000810

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

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

Apr 18, 2023

The c.217A>G (p.K73E) alteration is located in exon 2 (coding exon 2) of the ALDH2 gene. This alteration results from a A to G substitution at nucleotide position 217, causing the lysine (K) at amino acid position 73 to be replaced by a glutamic acid (E). 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	Benign	0.11
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.62	.;.;D
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	.;T;D
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.17	T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	-0.77	.;N;N
MutationTaster	Benign	0.86	D;D;N
PrimateAI	Uncertain	0.49	T
PROVEAN	Uncertain	-2.7	.;D;D
REVEL	Benign	0.077
Sift	Benign	0.047	.;D;D
Sift4G	Benign	0.47	T;T;T
Polyphen		0.0020	.;.;B
Vest4		0.39, 0.36
MutPred		0.46		.;Loss of ubiquitination at K73 (P = 0.0183);Loss of ubiquitination at K73 (P = 0.0183);
MVP		0.35
MPC		0.42
ClinPred		0.94	D
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.86
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.13
dbscSNV1_RF	Benign	0.40
SpliceAI score (max)		0.16		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs904582951; hg19: chr12-112219824;