rs2066702

Variant names:

• chr4-99307860-G-A
• rs2066702
• NM_000668.6:c.1108C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-99307860-G-A
• chr4-99307860-G-C

Variant summary

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

The NM_000668.6(ADH1B):​c.1108C>T​(p.Arg370Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0109 in 1,613,550 control chromosomes in the GnomAD database, including 1,461 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as protective (no stars).

• Frequency:
  • Genomes: 𝑓 0.054 (756 hom., cov: 32)
  • Exomes 𝑓: 0.0064 (705 hom.)
• Consequence: ADH1B NM_000668.6 missense
• Clinical Significance: protective no assertion criteria provided B:1
• Conservation: PhyloP100: 3.37
• Publications: 144 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0020994842).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.185 is higher than 0.05.

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.1108C>T	p.Arg370Cys	missense	Exon 9 of 9	NP_000659.2
	ADH1B	NM_001286650.2		c.988C>T	p.Arg330Cys	missense	Exon 10 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.1108C>T	p.Arg370Cys	missense	Exon 9 of 9	ENSP00000306606.8	P00325-1
	ADH1B	ENST00000625860.2	TSL:1	c.988C>T	p.Arg330Cys	missense	Exon 9 of 9	ENSP00000486614.1	P00325-2
	ADH1B	ENST00000881106.1		c.1141C>T	p.Arg381Cys	missense	Exon 9 of 9	ENSP00000551165.1

Frequencies

GnomAD3 genomes AF: 0.0545 AC: 8277 AN: 151978 Hom.: 757 Cov.: 32

Gnomad AFR AF: 0.189

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0171

Gnomad ASJ AF: 0.00634

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00156

Gnomad OTH AF: 0.0393

GnomAD2 exomes AF: 0.0150 AC: 3780 AN: 251340 AF XY: 0.0116

Gnomad AFR exome AF: 0.192

Gnomad AMR exome AF: 0.00885

Gnomad ASJ exome AF: 0.00823

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.00163

Gnomad OTH exome AF: 0.00766

GnomAD4 exome AF: 0.00638 AC: 9326 AN: 1461454 Hom.: 705 Cov.: 30 AF XY: 0.00566 AC XY: 4116 AN XY: 727070

African (AFR) AF: 0.197 AC: 6552 AN: 33286

American (AMR) AF: 0.00953 AC: 426 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00742 AC: 194 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39688

South Asian (SAS) AF: 0.00139 AC: 120 AN: 86248

European-Finnish (FIN) AF: 0.0000562 AC: 3 AN: 53408

Middle Eastern (MID) AF: 0.0102 AC: 59 AN: 5766

European-Non Finnish (NFE) AF: 0.00113 AC: 1255 AN: 1111854

Other (OTH) AF: 0.0119 AC: 716 AN: 60370

GnomAD4 genome AF: 0.0545 AC: 8286 AN: 152096 Hom.: 756 Cov.: 32 AF XY: 0.0529 AC XY: 3936 AN XY: 74364

African (AFR) AF: 0.188 AC: 7803 AN: 41458

American (AMR) AF: 0.0171 AC: 261 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00634 AC: 22 AN: 3468

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4812

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10600

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00156 AC: 106 AN: 67996

Other (OTH) AF: 0.0389 AC: 82 AN: 2106

Alfa AF: 0.0179 Hom.: 523

Bravo AF: 0.0624

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.187 AC: 824

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.0182 AC: 2205

Asia WGS AF: 0.00866 AC: 31 AN: 3478

EpiCase AF: 0.00207

EpiControl AF: 0.00302

ClinVar

ClinVar submissions

Significance: protective

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	-	Alcohol dependence (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.76
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.26
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.45
Eigen_PC	Benign	0.22
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-1.1	T
PhyloP100		3.4
PrimateAI	Benign	0.47	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.19
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.017	D
Vest4		0.32
MPC		0.83
ClinPred		0.10	T
GERP RS		3.1
gMVP		0.85
Mutation Taster		=72/28	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2066702; hg19: chr4-100229017; COSMIC: COSV105895189;