rs2302761

Variant names:

• chr17-7455201-C-T
• rs2302761
• NM_000747.3:c.1045-83C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000747.3(CHRNB1):​c.1045-83C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.201 in 1,470,170 control chromosomes in the GnomAD database, including 31,738 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2692 hom., cov: 30)
  • Exomes 𝑓: 0.20 (29046 hom.)
• Consequence: CHRNB1 NM_000747.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.101
• Publications: 18 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

ENSG00000308645 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 17-7455201-C-T is Benign according to our data. Variant chr17-7455201-C-T is described in ClinVar as Benign. ClinVar VariationId is 1293280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.266 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.1045-83C>T		intron_variant	Intron 8 of 10	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.1045-83C>T		intron_variant	Intron 8 of 10	1	NM_000747.3	ENSP00000304290.2

Frequencies

GnomAD3 genomes AF: 0.182 AC: 27591 AN: 151910 Hom.: 2697 Cov.: 30

Gnomad AFR AF: 0.159

Gnomad AMI AF: 0.285

Gnomad AMR AF: 0.145

Gnomad ASJ AF: 0.225

Gnomad EAS AF: 0.0357

Gnomad SAS AF: 0.279

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.205

Gnomad OTH AF: 0.201

GnomAD4 exome AF: 0.204 AC: 268521 AN: 1318142 Hom.: 29046 AF XY: 0.206 AC XY: 136928 AN XY: 663372

African (AFR) AF: 0.155 AC: 4738 AN: 30494

American (AMR) AF: 0.115 AC: 5094 AN: 44350

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 5754 AN: 25234

East Asian (EAS) AF: 0.0528 AC: 2059 AN: 39024

South Asian (SAS) AF: 0.274 AC: 22766 AN: 83034

European-Finnish (FIN) AF: 0.180 AC: 9580 AN: 53130

Middle Eastern (MID) AF: 0.266 AC: 1212 AN: 4556

European-Non Finnish (NFE) AF: 0.210 AC: 206038 AN: 982760

Other (OTH) AF: 0.203 AC: 11280 AN: 55560

GnomAD4 genome AF: 0.182 AC: 27595 AN: 152028 Hom.: 2692 Cov.: 30 AF XY: 0.180 AC XY: 13355 AN XY: 74304

African (AFR) AF: 0.159 AC: 6578 AN: 41460

American (AMR) AF: 0.145 AC: 2211 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 780 AN: 3470

East Asian (EAS) AF: 0.0357 AC: 185 AN: 5176

South Asian (SAS) AF: 0.279 AC: 1342 AN: 4814

European-Finnish (FIN) AF: 0.169 AC: 1791 AN: 10582

Middle Eastern (MID) AF: 0.255 AC: 75 AN: 294

European-Non Finnish (NFE) AF: 0.205 AC: 13954 AN: 67956

Other (OTH) AF: 0.199 AC: 420 AN: 2114

Alfa AF: 0.202 Hom.: 5933

Bravo AF: 0.179

Asia WGS AF: 0.144 AC: 504 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 07, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	12
DANN	Benign	0.85
PhyloP100		0.10
PromoterAI		0.040	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2302761; hg19: chr17-7358520; COSMIC: COSV107325883; COSMIC: COSV107325883;