12-111783212-C-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000690.4(ALDH2):c.274C>A(p.Pro92Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000624 in 1,613,488 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00068 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00062 (9 hom.)
• Consequence: ALDH2 NM_000690.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 3.78

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 Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013536364).
• BP6: Variant 12-111783212-C-A is Benign according to our data. Variant chr12-111783212-C-A is described in ClinVar as [Benign]. Clinvar id is 779154.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000619 (904/1461128) while in subpopulation AMR AF= 0.0193 (863/44656). AF 95% confidence interval is 0.0183. There are 9 homozygotes in gnomad4_exome. There are 367 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ALDH2	NM_000690.4	c.274C>A	p.Pro92Thr	missense_variant	3/13	ENST00000261733.7
ALDH2	NM_001204889.2	c.219+1190C>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ALDH2	ENST00000261733.7	c.274C>A	p.Pro92Thr	missense_variant	3/13	1	NM_000690.4	P1
ALDH2	ENST00000416293.7	c.219+1190C>A		intron_variant		2
ALDH2	ENST00000548536.1	c.*150C>A		3_prime_UTR_variant, NMD_transcript_variant	4/14	3

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152242 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00609

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: 0.0000294

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00307 AC: 768 AN: 250046 Hom.: 9 AF XY: 0.00217 AC XY: 294 AN XY: 135266

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0217

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000546

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00229

GnomAD4 exome AF: 0.000619 AC: 904 AN: 1461128 Hom.: 9 Cov.: 31 AF XY: 0.000505 AC XY: 367 AN XY: 726804

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.0193

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000540

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000676 AC: 103 AN: 152360 Hom.: 1 Cov.: 32 AF XY: 0.000671 AC XY: 50 AN XY: 74510

Gnomad4 AFR AF: 0.000144

Gnomad4 AMR AF: 0.00608

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0000351 Hom.: 0

Bravo AF: 0.00171

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00237 AC: 288

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.13
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Benign	-0.12
Eigen_PC	Benign	0.079
FATHMM_MKL	Pathogenic	0.98	D
MetaRNN	Benign	0.014	T;T
MetaSVM	Benign	-0.74	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.57	T
REVEL	Benign	0.28
Sift4G	Benign	0.092	T;T
Polyphen		0.019	.;B
Vest4		0.41
MVP		0.36
MPC		0.44
ClinPred		0.059	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.72
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs201582342; hg19: chr12-112221016; COSMIC: COSV55666796;