rs2302765

chr17-7447656-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000747.3(CHRNB1):c.610+6T>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.158 in 1,613,754 control chromosomes in the GnomAD database, including 21,213 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2289 hom., cov: 31)
  • Exomes 𝑓: 0.16 (18924 hom.)
• Consequence: CHRNB1 NM_000747.3 splice_donor_region, intron
• Scores: Splicing: ADA: 0.2278
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.29

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]

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-7447656-T-C is Benign according to our data. Variant chr17-7447656-T-C is described in ClinVar as [Benign]. Clinvar id is 128752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-7447656-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.205 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB1	NM_000747.3	c.610+6T>C		splice_donor_region_variant, intron_variant		ENST00000306071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB1	ENST00000306071.7	c.610+6T>C		splice_donor_region_variant, intron_variant		1	NM_000747.3	P1

Frequencies

GnomAD3 genomes AF: 0.166 AC: 25216 AN: 151940 Hom.: 2283 Cov.: 31

Gnomad AFR AF: 0.158

Gnomad AMI AF: 0.144

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.0999

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.152

GnomAD3 exomes AF: 0.175 AC: 44061 AN: 251400 Hom.: 4164 AF XY: 0.174 AC XY: 23640 AN XY: 135876

Gnomad AFR exome AF: 0.154

Gnomad AMR exome AF: 0.206

Gnomad ASJ exome AF: 0.101

Gnomad EAS exome AF: 0.190

Gnomad SAS exome AF: 0.219

Gnomad FIN exome AF: 0.244

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.167

GnomAD4 exome AF: 0.157 AC: 229039 AN: 1461694 Hom.: 18924 Cov.: 33 AF XY: 0.158 AC XY: 114756 AN XY: 727160

Gnomad4 AFR exome AF: 0.152

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.0997

Gnomad4 EAS exome AF: 0.201

Gnomad4 SAS exome AF: 0.216

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.146

Gnomad4 OTH exome AF: 0.159

GnomAD4 genome AF: 0.166 AC: 25250 AN: 152060 Hom.: 2289 Cov.: 31 AF XY: 0.172 AC XY: 12778 AN XY: 74344

Gnomad4 AFR AF: 0.157

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.0999

Gnomad4 EAS AF: 0.195

Gnomad4 SAS AF: 0.216

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.159

Alfa AF: 0.144 Hom.: 2133

Bravo AF: 0.160

Asia WGS AF: 0.270 AC: 936 AN: 3478

EpiCase AF: 0.131

EpiControl AF: 0.133

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 19, 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. -

Congenital myasthenic syndrome 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

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	-0.46
Cadd	Benign	19
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.23
dbscSNV1_RF	Benign	0.21
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

Publications

LitVar

Other links and lift over

dbSNP: rs2302765; hg19: chr17-7350975; COSMIC: COSV53439208; COSMIC: COSV53439208;