chr8-42756401-C-T

Variant names:

• chr8-42756401-C-T
• rs78464081
• NM_004198.3:c.798G>A

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_004198.3(CHRNA6):​c.798G>A​(p.Ser266Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000955 in 1,613,944 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (5 hom., cov: 32)
  • Exomes 𝑓: 0.00054 (7 hom.)
• Consequence: CHRNA6 NM_004198.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.66
• Publications: 1 publications found

Genes affected

CHRNA6 (HGNC:15963): (cholinergic receptor nicotinic alpha 6 subunit) This gene encodes an alpha subunit of neuronal nicotinic acetylcholine receptors. These receptors consist of five subunits and function as ion channels involved in neurotransmission. The encoded protein is a subunit of neuronal nicotinic acetylcholine receptors that mediate dopaminergic neurotransmission and are activated by acetylcholine and exogenous nicotine. Alternatively spliced transcript variants have been observed for this gene. Single nucleotide polymorphisms in this gene have been associated with both nicotine and alcohol dependence. [provided by RefSeq, Dec 2010]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 8-42756401-C-T is Benign according to our data. Variant chr8-42756401-C-T is described in ClinVar as Benign. ClinVar VariationId is 788868.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00497 (756/152060) while in subpopulation AFR AF = 0.0172 (712/41478). AF 95% confidence interval is 0.0161. There are 5 homozygotes in GnomAd4. There are 373 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004198.3. 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
	CHRNA6	NM_004198.3	MANE Select	c.798G>A	p.Ser266Ser	synonymous	Exon 5 of 6	NP_004189.1	Q15825-1
	CHRNA6	NM_001199279.1		c.753G>A	p.Ser251Ser	synonymous	Exon 4 of 5	NP_001186208.1	Q15825-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA6	ENST00000276410.7	TSL:1 MANE Select	c.798G>A	p.Ser266Ser	synonymous	Exon 5 of 6	ENSP00000276410.3	Q15825-1
	CHRNA6	ENST00000534622.5	TSL:2	c.753G>A	p.Ser251Ser	synonymous	Exon 4 of 5	ENSP00000433871.1	Q15825-2
	CHRNA6	ENST00000533810.5	TSL:4	c.*228G>A		downstream_gene	N/A	ENSP00000434659.1	E9PP97

Frequencies

GnomAD3 genomes AF: 0.00493 AC: 749 AN: 151942 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000736

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00129 AC: 324 AN: 251444 AF XY: 0.000876

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.000578

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000537 AC: 785 AN: 1461884 Hom.: 7 Cov.: 33 AF XY: 0.000465 AC XY: 338 AN XY: 727246

African (AFR) AF: 0.0194 AC: 648 AN: 33480

American (AMR) AF: 0.000626 AC: 28 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.0000315 AC: 35 AN: 1112008

Other (OTH) AF: 0.00113 AC: 68 AN: 60396

GnomAD4 genome AF: 0.00497 AC: 756 AN: 152060 Hom.: 5 Cov.: 32 AF XY: 0.00502 AC XY: 373 AN XY: 74358

African (AFR) AF: 0.0172 AC: 712 AN: 41478

American (AMR) AF: 0.00157 AC: 24 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10570

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000736 AC: 5 AN: 67972

Other (OTH) AF: 0.00664 AC: 14 AN: 2110

Alfa AF: 0.00409 Hom.: 1

Bravo AF: 0.00543

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

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	-0.78
CADD	Benign	4.9
DANN	Benign	0.65
PhyloP100		-1.7
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs78464081; hg19: chr8-42611544; COSMIC: COSV52380663; COSMIC: COSV52380663;