chr17-7457004-T-C

Variant names:

Variant summary

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

-12

BP4_StrongBA1

The NM_000747.3(CHRNB1):c.*281T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.165 in 455,056 control chromosomes in the GnomAD database, including 6,688 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 0.16 ( 2209 hom., cov: 32)

Exomes 𝑓: 0.17 ( 4479 hom. )

Consequence

CHRNB1
NM_000747.3 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.741

Publications

11 publications found

Variant links:

Genes affected

CHRNB1 (HGNC:1961): (cholinergic receptor nicotinic beta 1 subunit) The muscle acetylcholine receptor is composed of five subunits: two alpha subunits and one beta, one gamma, and one delta subunit. This gene encodes the beta subunit of the acetylcholine receptor. The acetylcholine receptor changes conformation upon acetylcholine binding leading to the opening of an ion-conducting channel across the plasma membrane. Mutations in this gene are associated with slow-channel congenital myasthenic syndrome. [provided by RefSeq, Jul 2008]

CHRNB1 Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 2C
Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
congenital myasthenic syndrome 1A
Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
congenital myasthenic syndrome 2A
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
postsynaptic congenital myasthenic syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

CHRNB1 links:

Genome browser will be placed here

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=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3 link	c.*281T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000306071.7	NP_000738.2	P11230-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
CHRNB1	ENST00000306071.7 link	c.*281T>C	3_prime_UTR_variant	Exon 11 of 11	1	NM_000747.3	ENSP00000304290.2	P11230-1
CHRNB1	ENST00000576360.1 link	c.*281T>C	3_prime_UTR_variant	Exon 10 of 10	3		ENSP00000459092.1	I3L1T7
CHRNB1	ENST00000575379.1 link	c.*281T>C	3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000461751.1	I3L535
CHRNB1	ENST00000536404.6 link	c.*281T>C	downstream_gene_variant		2		ENSP00000439209.2	P11230-2

Frequencies

GnomAD3 genomes

AF:

0.163

AC:

24828

AN:

151992

Hom.:

2198

Cov.:

show subpopulations

Gnomad AFR

AF:

0.148

Gnomad AMI

AF:

0.145

Gnomad AMR

AF:

0.196

Gnomad ASJ

AF:

0.100

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.212

Gnomad FIN

AF:

0.246

Gnomad MID

AF:

0.0949

Gnomad NFE

AF:

0.151

Gnomad OTH

AF:

0.153

GnomAD4 exome

AF:

0.166

AC:

50407

AN:

302944

Hom.:

4479

Cov.:

AF XY:

0.168

AC XY:

27096

AN XY:

161652

show subpopulations

African (AFR)

AF:

0.137

AC:

1216

AN:

8896

American (AMR)

AF:

0.208

AC:

2883

AN:

13828

Ashkenazi Jewish (ASJ)

AF:

0.0984

AC:

870

AN:

8838

East Asian (EAS)

AF:

0.199

AC:

3394

AN:

17030

South Asian (SAS)

AF:

0.211

AC:

8683

AN:

41214

European-Finnish (FIN)

AF:

0.239

AC:

3869

AN:

16174

Middle Eastern (MID)

AF:

0.0795

AC:

AN:

1220

European-Non Finnish (NFE)

AF:

0.149

AC:

26673

AN:

178794

Other (OTH)

AF:

0.161

AC:

2722

AN:

16950

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

2017

4033

6050

8066

10083

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

216

432

648

864

1080

<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:

0.163

AC:

24858

AN:

152112

Hom.:

2209

Cov.:

AF XY:

0.169

AC XY:

12576

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.148

AC:

6132

AN:

41510

American (AMR)

AF:

0.197

AC:

3008

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.100

AC:

348

AN:

3468

East Asian (EAS)

AF:

0.196

AC:

1011

AN:

5168

South Asian (SAS)

AF:

0.213

AC:

1027

AN:

4822

European-Finnish (FIN)

AF:

0.246

AC:

2597

AN:

10560

Middle Eastern (MID)

AF:

0.0918

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.151

AC:

10238

AN:

67982

Other (OTH)

AF:

0.160

AC:

338

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1044

2088

3133

4177

5221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

274

548

822

1096

1370

<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:

0.146

Hom.:

2186

Bravo

AF:

0.157

Asia WGS

AF:

0.269

AC:

934

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 28, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Congenital myasthenic syndrome 4C

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

(source)

DANN

Benign

0.31

PhyloP100

0.74

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over