chr12-111767010-C-T

Variant names:

• chr12-111767010-C-T
• NM_000690.4:c.28C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000690.4(ALDH2):​c.28C>T​(p.Pro10Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000729 in 1,371,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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: 7.3e-7 (0 hom.)
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.25
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10753438).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000690.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	NM_000690.4	MANE Select	c.28C>T	p.Pro10Ser	missense	Exon 1 of 13	NP_000681.2
	ALDH2	NM_001204889.2		c.28C>T	p.Pro10Ser	missense	Exon 1 of 12	NP_001191818.1	P05091-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ALDH2	ENST00000261733.7	TSL:1 MANE Select	c.28C>T	p.Pro10Ser	missense	Exon 1 of 13	ENSP00000261733.2	P05091-1
	ENSG00000257767	ENST00000546840.3	TSL:5	c.102+11265C>T		intron	N/A	ENSP00000450353.4	F8VP50
	ALDH2	ENST00000871406.1		c.28C>T	p.Pro10Ser	missense	Exon 1 of 14	ENSP00000541465.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.29e-7 AC: 1 AN: 1371598 Hom.: 0 Cov.: 30 AF XY: 0.00000148 AC XY: 1 AN XY: 676856

African (AFR) AF: 0.00 AC: 0 AN: 29160

American (AMR) AF: 0.00 AC: 0 AN: 34864

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24520

East Asian (EAS) AF: 0.00 AC: 0 AN: 33886

South Asian (SAS) AF: 0.0000128 AC: 1 AN: 78122

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34964

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4896

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073910

Other (OTH) AF: 0.00 AC: 0 AN: 57276

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	18
DANN	Benign	0.83
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.67	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.3	L
PhyloP100		1.3
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	-0.20	N
REVEL	Benign	0.12
Sift	Benign	0.17	T
Sift4G	Benign	0.28	T
Polyphen		0.0010	B
Vest4		0.21
MutPred		0.27		Gain of helix (P = 0.0022)
MVP		0.64
MPC		0.30
ClinPred		0.17	T
GERP RS		1.6
PromoterAI		-0.14	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.059
gMVP		0.52
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

hg19: chr12-112204814;