chr12-111799980-G-A
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Variant summary
Our verdict is Benign. Variant got -9 ACMG points: 2P and 11B. PM2BP4_ModerateBP6_Very_StrongBP7
The NM_000690.4(ALDH2):c.1323G>A(p.Thr441=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000151 in 1,613,996 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Genomes: 𝑓 0.00080 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000083 ( 1 hom. )
Consequence
ALDH2
NM_000690.4 synonymous
NM_000690.4 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 0.491
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]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -9 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.32).
BP6
Variant 12-111799980-G-A is Benign according to our data. Variant chr12-111799980-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 746328.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=0.491 with no splicing effect.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
ALDH2 | NM_000690.4 | c.1323G>A | p.Thr441= | synonymous_variant | 11/13 | ENST00000261733.7 | |
ALDH2 | NM_001204889.2 | c.1182G>A | p.Thr394= | synonymous_variant | 10/12 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
ALDH2 | ENST00000261733.7 | c.1323G>A | p.Thr441= | synonymous_variant | 11/13 | 1 | NM_000690.4 | P1 | |
ALDH2 | ENST00000416293.7 | c.1182G>A | p.Thr394= | synonymous_variant | 10/12 | 2 | |||
ALDH2 | ENST00000548536.1 | c.*1199G>A | 3_prime_UTR_variant, NMD_transcript_variant | 12/14 | 3 | ||||
ALDH2 | ENST00000549106.1 | c.337+1738G>A | intron_variant, NMD_transcript_variant | 3 |
Frequencies
GnomAD3 genomes AF: 0.000801 AC: 122AN: 152224Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000243 AC: 61AN: 250658Hom.: 0 AF XY: 0.000170 AC XY: 23AN XY: 135664
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GnomAD4 exome AF: 0.0000835 AC: 122AN: 1461654Hom.: 1 Cov.: 30 AF XY: 0.0000701 AC XY: 51AN XY: 727096
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GnomAD4 genome AF: 0.000801 AC: 122AN: 152342Hom.: 0 Cov.: 32 AF XY: 0.000711 AC XY: 53AN XY: 74510
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Invitae | Mar 29, 2018 | - - |
ALDH2-related disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Mar 01, 2019 | This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). - |
Computational scores
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BayesDel_noAF
Benign
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Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
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Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at