chr17-7447656-T-C

Variant names:

• chr17-7447656-T-C
• rs2302765
• NM_000747.3:c.610+6T>C

Variant summary

Our verdict is Benign. The variant received -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 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. 3/3 splice prediction tools predict no significant impact on normal splicing. 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_region, intron
• Scores: Splicing: ADA: 0.2278
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.29
• Publications: 19 publications found

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

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 128752.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.610+6T>C		splice_region_variant, intron_variant	Intron 6 of 10	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.610+6T>C		splice_region_variant, intron_variant	Intron 6 of 10	1	NM_000747.3	ENSP00000304290.2

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

GnomAD2 exomes AF: 0.175 AC: 44061 AN: 251400 AF XY: 0.174

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 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

African (AFR) AF: 0.152 AC: 5095 AN: 33478

American (AMR) AF: 0.207 AC: 9269 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0997 AC: 2606 AN: 26134

East Asian (EAS) AF: 0.201 AC: 7988 AN: 39698

South Asian (SAS) AF: 0.216 AC: 18650 AN: 86254

European-Finnish (FIN) AF: 0.239 AC: 12742 AN: 53402

Middle Eastern (MID) AF: 0.0806 AC: 465 AN: 5768

European-Non Finnish (NFE) AF: 0.146 AC: 162630 AN: 1111850

Other (OTH) AF: 0.159 AC: 9594 AN: 60388

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

African (AFR) AF: 0.157 AC: 6524 AN: 41472

American (AMR) AF: 0.197 AC: 3010 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0999 AC: 347 AN: 3472

East Asian (EAS) AF: 0.195 AC: 1007 AN: 5170

South Asian (SAS) AF: 0.216 AC: 1039 AN: 4814

European-Finnish (FIN) AF: 0.246 AC: 2598 AN: 10574

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10236 AN: 67970

Other (OTH) AF: 0.159 AC: 334 AN: 2106

Alfa AF: 0.145 Hom.: 2631

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Aug 15, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 19, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 2A Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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	-0.46
CADD	Benign	19
DANN	Benign	0.74
PhyloP100		2.3
Mutation Taster		=80/20	polymorphism (auto)

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

Other links and lift over

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