12-111767072-G-T

Position:

• chr12-111767072-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000690.4(ALDH2):​c.90G>T​(p.Gln30His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.26

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.093444586).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.90G>T	p.Gln30His	missense_variant	1/13	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.90G>T	p.Gln30His	missense_variant	1/12		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.90G>T	p.Gln30His	missense_variant	1/13	1	NM_000690.4	ENSP00000261733	P1
ALDH2	ENST00000416293.7	c.90G>T	p.Gln30His	missense_variant	1/12	2		ENSP00000403349
ALDH2	ENST00000548536.1	c.90G>T	p.Gln30His	missense_variant, NMD_transcript_variant	1/14	3		ENSP00000448179

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1374266 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 678670

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: 0.00

Gnomad4 OTH exome AF: 0.00

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

Mar 07, 2023

The c.90G>T (p.Q30H) alteration is located in exon 1 (coding exon 1) of the ALDH2 gene. This alteration results from a G to T substitution at nucleotide position 90, causing the glutamine (Q) at amino acid position 30 to be replaced by a histidine (H). 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	0.16
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	20
DANN	Benign	0.85
DEOGEN2	Benign	0.34	.;T
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.75	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.093	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.69	N;N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.036
Sift	Benign	0.12	T;T
Sift4G	Benign	0.12	T;T
Polyphen		0.0	.;B
Vest4		0.26
MutPred		0.20		Loss of glycosylation at P28 (P = 0.0921);Loss of glycosylation at P28 (P = 0.0921);
MVP		0.22
MPC		0.28
ClinPred		0.13	T
GERP RS		2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.28
gMVP		0.39

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-112204876;