rs2298753

Variant names:

• chr4-99336750-T-C
• rs2298753
• NM_000669.5:c.*2A>G

Your query was ambiguous. Multiple possible variants found:

• chr4-99336750-T-C
• chr4-99336750-T-G

Variant summary

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

The NM_000669.5(ADH1C):​c.*2A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0959 in 1,613,352 control chromosomes in the GnomAD database, including 8,000 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 0.079 (579 hom., cov: 32)
  • Exomes 𝑓: 0.098 (7421 hom.)
• Consequence: ADH1C NM_000669.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.493
• Publications: 17 publications found

Genes affected

ADH1C (HGNC:251): (alcohol dehydrogenase 1C (class I), gamma polypeptide) This gene encodes class I alcohol dehydrogenase, gamma subunit, which is a member of the alcohol dehydrogenase family. Members of this enzyme family metabolize a wide variety of substrates, including ethanol, retinol, other aliphatic alcohols, hydroxysteroids, and lipid peroxidation products. Class I alcohol dehydrogenase, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation to acetaldehyde, thus playing a major role in ethanol catabolism. Three genes encoding alpha, beta and gamma subunits are tandemly organized in a genomic segment as a gene cluster. An association between ADH1C polymorphism and alcohol dependence has not been established. [provided by RefSeq, Sep 2019]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADH1C	NM_000669.5	c.*2A>G		3_prime_UTR_variant	Exon 9 of 9	ENST00000515683.6	NP_000660.1
ADH1C	NR_133005.2	n.1157A>G		non_coding_transcript_exon_variant	Exon 9 of 9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADH1C	ENST00000515683.6	c.*2A>G		3_prime_UTR_variant	Exon 9 of 9	1	NM_000669.5	ENSP00000426083.1

Frequencies

GnomAD3 genomes AF: 0.0794 AC: 12079 AN: 152100 Hom.: 572 Cov.: 32

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.0947

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.0602

Gnomad SAS AF: 0.100

Gnomad FIN AF: 0.141

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0718

GnomAD2 exomes AF: 0.101 AC: 25338 AN: 251172 AF XY: 0.0995

Gnomad AFR exome AF: 0.0257

Gnomad AMR exome AF: 0.152

Gnomad ASJ exome AF: 0.0528

Gnomad EAS exome AF: 0.0575

Gnomad FIN exome AF: 0.147

Gnomad NFE exome AF: 0.0981

Gnomad OTH exome AF: 0.0869

GnomAD4 exome AF: 0.0976 AC: 142609 AN: 1461134 Hom.: 7421 Cov.: 31 AF XY: 0.0968 AC XY: 70379 AN XY: 726874

African (AFR) AF: 0.0223 AC: 746 AN: 33448

American (AMR) AF: 0.143 AC: 6398 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.0537 AC: 1403 AN: 26120

East Asian (EAS) AF: 0.0496 AC: 1967 AN: 39680

South Asian (SAS) AF: 0.105 AC: 9031 AN: 86226

European-Finnish (FIN) AF: 0.143 AC: 7625 AN: 53398

Middle Eastern (MID) AF: 0.0622 AC: 358 AN: 5760

European-Non Finnish (NFE) AF: 0.0984 AC: 109416 AN: 1111482

Other (OTH) AF: 0.0938 AC: 5665 AN: 60368

GnomAD4 genome AF: 0.0794 AC: 12087 AN: 152218 Hom.: 579 Cov.: 32 AF XY: 0.0817 AC XY: 6082 AN XY: 74418

African (AFR) AF: 0.0269 AC: 1119 AN: 41544

American (AMR) AF: 0.0947 AC: 1447 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3470

East Asian (EAS) AF: 0.0597 AC: 309 AN: 5174

South Asian (SAS) AF: 0.100 AC: 482 AN: 4816

European-Finnish (FIN) AF: 0.141 AC: 1500 AN: 10602

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6855 AN: 68012

Other (OTH) AF: 0.0767 AC: 162 AN: 2112

Alfa AF: 0.0649 Hom.: 316

Bravo AF: 0.0741

Asia WGS AF: 0.107 AC: 370 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.7
DANN	Benign	0.62
PhyloP100		-0.49

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: rs2298753; hg19: chr4-100257907; COSMIC: COSV72892957;