rs2018417

Variant names:

• chr4-99313983-C-A
• rs2018417
• NM_000668.6:c.666G>T

Your query was ambiguous. Multiple possible variants found:

• chr4-99313983-C-A
• chr4-99313983-C-G
• chr4-99313983-C-T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000668.6(ADH1B):​c.666G>T​(p.Ala222Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.031 in 1,613,964 control chromosomes in the GnomAD database, including 908 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (75 hom., cov: 32)
  • Exomes 𝑓: 0.031 (833 hom.)
• Consequence: ADH1B NM_000668.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.70
• Publications: 11 publications found

Genes affected

ADH1B (HGNC:250): (alcohol dehydrogenase 1B (class I), beta polypeptide) The protein encoded by this gene 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. This encoded protein, consisting of several homo- and heterodimers of alpha, beta, and gamma subunits, exhibits high activity for ethanol oxidation and plays 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. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2013]

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-99313983-C-A is Benign according to our data. Variant chr4-99313983-C-A is described in ClinVar as Benign. ClinVar VariationId is 769290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.7 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0292 (4451/152230) while in subpopulation AFR AF = 0.035 (1454/41538). AF 95% confidence interval is 0.0335. There are 75 homozygotes in GnomAd4. There are 2122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 75 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000668.6. 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
	ADH1B	NM_000668.6	MANE Select	c.666G>T	p.Ala222Ala	synonymous	Exon 6 of 9	NP_000659.2
	ADH1B	NM_001286650.2		c.546G>T	p.Ala182Ala	synonymous	Exon 7 of 10	NP_001273579.1	D6RHZ6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADH1B	ENST00000305046.13	TSL:1 MANE Select	c.666G>T	p.Ala222Ala	synonymous	Exon 6 of 9	ENSP00000306606.8	P00325-1
	ADH1B	ENST00000625860.2	TSL:1	c.546G>T	p.Ala182Ala	synonymous	Exon 6 of 9	ENSP00000486614.1	P00325-2
	ADH1B	ENST00000881106.1		c.666G>T	p.Ala222Ala	synonymous	Exon 6 of 9	ENSP00000551165.1

Frequencies

GnomAD3 genomes AF: 0.0292 AC: 4442 AN: 152112 Hom.: 75 Cov.: 32

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0146

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0135

Gnomad FIN AF: 0.0345

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0330

Gnomad OTH AF: 0.0244

GnomAD2 exomes AF: 0.0222 AC: 5555 AN: 250462 AF XY: 0.0221

Gnomad AFR exome AF: 0.0322

Gnomad AMR exome AF: 0.00825

Gnomad ASJ exome AF: 0.0113

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0338

Gnomad NFE exome AF: 0.0293

Gnomad OTH exome AF: 0.0193

GnomAD4 exome AF: 0.0312 AC: 45613 AN: 1461734 Hom.: 833 Cov.: 33 AF XY: 0.0305 AC XY: 22203 AN XY: 727170

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0352 AC: 1177 AN: 33474

American (AMR) AF: 0.00915 AC: 409 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0146 AC: 382 AN: 26132

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0182 AC: 1567 AN: 86246

European-Finnish (FIN) AF: 0.0359 AC: 1919 AN: 53420

Middle Eastern (MID) AF: 0.0283 AC: 163 AN: 5766

European-Non Finnish (NFE) AF: 0.0346 AC: 38507 AN: 1111886

Other (OTH) AF: 0.0246 AC: 1487 AN: 60390

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0292 AC: 4451 AN: 152230 Hom.: 75 Cov.: 32 AF XY: 0.0285 AC XY: 2122 AN XY: 74420

African (AFR) AF: 0.0350 AC: 1454 AN: 41538

American (AMR) AF: 0.0146 AC: 223 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0133 AC: 64 AN: 4818

European-Finnish (FIN) AF: 0.0345 AC: 365 AN: 10590

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0330 AC: 2247 AN: 68024

Other (OTH) AF: 0.0241 AC: 51 AN: 2112

Alfa AF: 0.0232 Hom.: 20

Bravo AF: 0.0279

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	0.61
DANN	Benign	0.56
PhyloP100		-2.7
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: rs2018417; hg19: chr4-100235140; COSMIC: COSV59296113; COSMIC: COSV59296113;