12-111792160-G-A

Variant summary

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

The NM_000690.4(ALDH2):c.895G>A(p.Asp299Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000121 in 1,598,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000087 (0 hom.)
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.32

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=0.15868127).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH2	NM_000690.4	c.895G>A	p.Asp299Asn	missense_variant	8/13	ENST00000261733.7
ALDH2	NM_001204889.2	c.754G>A	p.Asp252Asn	missense_variant	7/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH2	ENST00000261733.7	c.895G>A	p.Asp299Asn	missense_variant	8/13	1	NM_000690.4	P1
ALDH2	ENST00000416293.7	c.754G>A	p.Asp252Asn	missense_variant	7/12	2
ALDH2	ENST00000548536.1	c.*771G>A		3_prime_UTR_variant, NMD_transcript_variant	9/14	3

Frequencies

GnomAD3 genomes AF: 0.000434 AC: 66 AN: 152240 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00125

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000123 AC: 29 AN: 236218 Hom.: 0 AF XY: 0.000101 AC XY: 13 AN XY: 128322

Gnomad AFR exome AF: 0.00101

Gnomad AMR exome AF: 0.000171

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000252

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000871 AC: 126 AN: 1446480 Hom.: 0 Cov.: 30 AF XY: 0.0000931 AC XY: 67 AN XY: 719892

Gnomad4 AFR exome AF: 0.000931

Gnomad4 AMR exome AF: 0.000152

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000323

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000488

Gnomad4 OTH exome AF: 0.000134

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152358 Hom.: 0 Cov.: 32 AF XY: 0.000483 AC XY: 36 AN XY: 74502

Gnomad4 AFR AF: 0.00127

Gnomad4 AMR AF: 0.000588

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000844 Hom.: 0

Bravo AF: 0.000514

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.0000545

EpiControl AF: 0.0000594

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

Aug 30, 2021

The c.895G>A (p.D299N) alteration is located in exon 8 (coding exon 8) of the ALDH2 gene. This alteration results from a G to A substitution at nucleotide position 895, causing the aspartic acid (D) at amino acid position 299 to be replaced by an asparagine (N). 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	0.12
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	23
Dann	Uncertain	1.0
Eigen	Benign	0.15
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.16	T;T
MetaSVM	Uncertain	0.20	D
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.79	T
PROVEAN	Pathogenic	-4.4	D;D
REVEL	Uncertain	0.43
Sift	Benign	0.069	T;T
Sift4G	Benign	0.086	T;T
Polyphen		0.64	.;P
Vest4		0.40
MVP		0.97
MPC		0.35
ClinPred		0.076	T
GERP RS		5.4
Varity_R		0.57
gMVP		0.50

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

LitVar

Other links and lift over

dbSNP: rs142271678; hg19: chr12-112229964;