Genetic Variant NM_004198.3:c.1354-126G>A (chr8-42753436-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004198.3(CHRNA6):c.1354-126G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.242 in 872,060 control chromosomes in the GnomAD database, including 33,809 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 0.36 ( 13881 hom., cov: 32)

Exomes 𝑓: 0.22 ( 19928 hom. )

Consequence

CHRNA6
NM_004198.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.34

Publications

4 publications found

Variant links:

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]

CHRNA6 links:

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ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.93).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.723 is higher than 0.05.

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.1354-126G>A		intron	N/A	NP_004189.1
	CHRNA6	NM_001199279.1		c.1309-126G>A		intron	N/A	NP_001186208.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNA6	ENST00000276410.7	TSL:1 MANE Select	c.1354-126G>A		intron	N/A	ENSP00000276410.3
	CHRNA6	ENST00000534622.5	TSL:2	c.1309-126G>A		intron	N/A	ENSP00000433871.1

Frequencies

GnomAD3 genomes

AF:

0.355

AC:

53977

AN:

151980

Hom.:

13832

Cov.:

show subpopulations

Gnomad AFR

AF:

0.729

Gnomad AMI

AF:

0.102

Gnomad AMR

AF:

0.274

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.214

Gnomad SAS

AF:

0.206

Gnomad FIN

AF:

0.186

Gnomad MID

AF:

0.215

Gnomad NFE

AF:

0.205

Gnomad OTH

AF:

0.323

GnomAD4 exome

AF:

0.219

AC:

157324

AN:

719962

Hom.:

19928

AF XY:

0.216

AC XY:

82604

AN XY:

382100

show subpopulations

African (AFR)

AF:

0.739

AC:

12659

AN:

17140

American (AMR)

AF:

0.243

AC:

6440

AN:

26470

Ashkenazi Jewish (ASJ)

AF:

0.220

AC:

3911

AN:

17804

East Asian (EAS)

AF:

0.186

AC:

6206

AN:

33452

South Asian (SAS)

AF:

0.209

AC:

12910

AN:

61828

European-Finnish (FIN)

AF:

0.195

AC:

7586

AN:

38928

Middle Eastern (MID)

AF:

0.241

AC:

617

AN:

2556

European-Non Finnish (NFE)

AF:

0.202

AC:

98637

AN:

487324

Other (OTH)

AF:

0.243

AC:

8358

AN:

34460

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

5908

11817

17725

23634

29542

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2172

4344

6516

8688

10860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.356

AC:

54086

AN:

152098

Hom.:

13881

Cov.:

AF XY:

0.349

AC XY:

25969

AN XY:

74360

show subpopulations

African (AFR)

AF:

0.730

AC:

30310

AN:

41514

American (AMR)

AF:

0.274

AC:

4173

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

769

AN:

3472

East Asian (EAS)

AF:

0.213

AC:

1103

AN:

5170

South Asian (SAS)

AF:

0.205

AC:

987

AN:

4818

European-Finnish (FIN)

AF:

0.186

AC:

1968

AN:

10592

Middle Eastern (MID)

AF:

0.221

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.205

AC:

13935

AN:

67960

Other (OTH)

AF:

0.324

AC:

683

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1389

2778

4166

5555

6944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

456

912

1368

1824

2280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.312

Hom.:

1356

Bravo

AF:

0.380

Asia WGS

AF:

0.270

AC:

939

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.93

CADD

Benign

0.35

(source)

DANN

Benign

0.43

PhyloP100

-1.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over