rs76001008

Positions:

chr17-7454288-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000747.3(CHRNB1):c.821-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,605,916 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.014 ( 26 hom., cov: 30)

Exomes 𝑓: 0.019 ( 295 hom. )

Consequence

CHRNB1
NM_000747.3 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002066

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.925

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.7).

BP6

Variant 17-7454288-C-T is Benign according to our data. Variant chr17-7454288-C-T is described in ClinVar as [Benign]. Clinvar id is 128753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7454288-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0137 (2088/152276) while in subpopulation NFE AF= 0.0211 (1436/68014). AF 95% confidence interval is 0.0202. There are 26 homozygotes in gnomad4. There are 963 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 26 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB1	NM_000747.3 linkuse as main transcript	c.821-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7 linkuse as main transcript	c.821-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000747.3	ENSP00000304290	P1	P11230-1

Frequencies

GnomAD3 genomes

AF:

0.0137

AC:

2087

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00372

Gnomad AMI

AF:

0.0473

Gnomad AMR

AF:

0.00851

Gnomad ASJ

AF:

0.0452

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00642

Gnomad FIN

AF:

0.00904

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0211

Gnomad OTH

AF:

0.0172

GnomAD3 exomes

AF:

0.0147

AC:

3684

AN:

251452

Hom.:

AF XY:

0.0150

AC XY:

2041

AN XY:

135902

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00743

Gnomad ASJ exome

AF:

0.0399

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00542

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0199

GnomAD4 exome

AF:

0.0185

AC:

26935

AN:

1453640

Hom.:

295

Cov.:

AF XY:

0.0184

AC XY:

13324

AN XY:

723748

show subpopulations

Gnomad4 AFR exome

AF:

0.00270

Gnomad4 AMR exome

AF:

0.00805

Gnomad4 ASJ exome

AF:

0.0412

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.00495

Gnomad4 FIN exome

AF:

0.0119

Gnomad4 NFE exome

AF:

0.0210

Gnomad4 OTH exome

AF:

0.0173

GnomAD4 genome

AF:

0.0137

AC:

2088

AN:

152276

Hom.:

Cov.:

AF XY:

0.0129

AC XY:

963

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00371

Gnomad4 AMR

AF:

0.00850

Gnomad4 ASJ

AF:

0.0452

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00643

Gnomad4 FIN

AF:

0.00904

Gnomad4 NFE

AF:

0.0211

Gnomad4 OTH

AF:

0.0170

Alfa

AF:

0.0201

Hom.:

Bravo

AF:

0.0138

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.0237

EpiControl

AF:

0.0220

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	May 18, 2021	- -

Congenital myasthenic syndrome 2A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

not provided

Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Congenital myasthenic syndrome 4C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

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

-0.70

CADD

Benign

DANN

Benign

0.78

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000021

dbscSNV1_RF

Benign

0.014

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over