chr12-111797979-C-A

Variant names:

• chr12-111797979-C-A
• rs4646778
• NM_000690.4:c.1084-99C>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000690.4(ALDH2):​c.1084-99C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.175 in 1,428,688 control chromosomes in the GnomAD database, including 22,423 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.18 (2494 hom., cov: 32)
  • Exomes 𝑓: 0.17 (19929 hom.)
• Consequence: ALDH2 NM_000690.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.108
• Publications: 22 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]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.223 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ALDH2	NM_000690.4	c.1084-99C>A		intron_variant	Intron 9 of 12	ENST00000261733.7	NP_000681.2
ALDH2	NM_001204889.2	c.943-99C>A		intron_variant	Intron 8 of 11		NP_001191818.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ALDH2	ENST00000261733.7	c.1084-99C>A		intron_variant	Intron 9 of 12	1	NM_000690.4	ENSP00000261733.2
ALDH2	ENST00000416293.7	c.943-99C>A		intron_variant	Intron 8 of 11	2		ENSP00000403349.3
ALDH2	ENST00000548536.1	n.*960-99C>A		intron_variant	Intron 10 of 13	3		ENSP00000448179.1
ALDH2	ENST00000549106.1	n.172-99C>A		intron_variant	Intron 1 of 3	3		ENSP00000474669.1

Frequencies

GnomAD3 genomes AF: 0.178 AC: 27085 AN: 151972 Hom.: 2496 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.0911

Gnomad EAS AF: 0.234

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.152

Gnomad MID AF: 0.275

Gnomad NFE AF: 0.168

Gnomad OTH AF: 0.189

GnomAD4 exome AF: 0.175 AC: 222800 AN: 1276598 Hom.: 19929 AF XY: 0.174 AC XY: 111600 AN XY: 639758

African (AFR) AF: 0.197 AC: 5834 AN: 29668

American (AMR) AF: 0.170 AC: 6440 AN: 37838

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2453 AN: 24274

East Asian (EAS) AF: 0.185 AC: 6961 AN: 37718

South Asian (SAS) AF: 0.213 AC: 16678 AN: 78294

European-Finnish (FIN) AF: 0.155 AC: 7452 AN: 48160

Middle Eastern (MID) AF: 0.255 AC: 1353 AN: 5312

European-Non Finnish (NFE) AF: 0.173 AC: 166099 AN: 961104

Other (OTH) AF: 0.176 AC: 9530 AN: 54230

GnomAD4 genome AF: 0.178 AC: 27081 AN: 152090 Hom.: 2494 Cov.: 32 AF XY: 0.177 AC XY: 13135 AN XY: 74342

African (AFR) AF: 0.199 AC: 8235 AN: 41470

American (AMR) AF: 0.173 AC: 2637 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.0911 AC: 316 AN: 3468

East Asian (EAS) AF: 0.234 AC: 1211 AN: 5180

South Asian (SAS) AF: 0.211 AC: 1017 AN: 4820

European-Finnish (FIN) AF: 0.152 AC: 1605 AN: 10590

Middle Eastern (MID) AF: 0.269 AC: 79 AN: 294

European-Non Finnish (NFE) AF: 0.168 AC: 11457 AN: 67998

Other (OTH) AF: 0.186 AC: 392 AN: 2112

Alfa AF: 0.173 Hom.: 3718

Bravo AF: 0.182

Asia WGS AF: 0.248 AC: 863 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.1
DANN	Benign	0.57
PhyloP100		-0.11
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs4646778; hg19: chr12-112235783; COSMIC: COSV55671112; COSMIC: COSV55671112;