17-7455542-T-C

Variant names:

• chr17-7455542-T-C
• rs2302762
• NM_000747.3:c.1217+86T>C

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.1217+86T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.681 in 1,527,408 control chromosomes in the GnomAD database, including 364,322 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.60 (29290 hom., cov: 32)
  • Exomes 𝑓: 0.69 (335032 hom.)
• Consequence: CHRNB1 NM_000747.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0870
• 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=-0.96).
• BP6: Variant 17-7455542-T-C is Benign according to our data. Variant chr17-7455542-T-C is described in ClinVar as Benign. ClinVar VariationId is 679143.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.718 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.1217+86T>C		intron_variant	Intron 9 of 10	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.1217+86T>C		intron_variant	Intron 9 of 10	1	NM_000747.3	ENSP00000304290.2

Frequencies

GnomAD3 genomes AF: 0.602 AC: 91496 AN: 151914 Hom.: 29290 Cov.: 32

Gnomad AFR AF: 0.420

Gnomad AMI AF: 0.820

Gnomad AMR AF: 0.582

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.233

Gnomad SAS AF: 0.609

Gnomad FIN AF: 0.692

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.723

Gnomad OTH AF: 0.645

GnomAD4 exome AF: 0.690 AC: 948653 AN: 1375376 Hom.: 335032 Cov.: 21 AF XY: 0.689 AC XY: 474074 AN XY: 688348

African (AFR) AF: 0.398 AC: 12552 AN: 31520

American (AMR) AF: 0.500 AC: 22021 AN: 44052

Ashkenazi Jewish (ASJ) AF: 0.679 AC: 17402 AN: 25634

East Asian (EAS) AF: 0.255 AC: 9986 AN: 39200

South Asian (SAS) AF: 0.615 AC: 51655 AN: 83952

European-Finnish (FIN) AF: 0.700 AC: 37008 AN: 52876

Middle Eastern (MID) AF: 0.678 AC: 3135 AN: 4624

European-Non Finnish (NFE) AF: 0.730 AC: 756726 AN: 1036062

Other (OTH) AF: 0.664 AC: 38168 AN: 57456

GnomAD4 genome AF: 0.602 AC: 91514 AN: 152032 Hom.: 29290 Cov.: 32 AF XY: 0.598 AC XY: 44415 AN XY: 74296

African (AFR) AF: 0.419 AC: 17376 AN: 41458

American (AMR) AF: 0.582 AC: 8883 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2347 AN: 3470

East Asian (EAS) AF: 0.233 AC: 1208 AN: 5180

South Asian (SAS) AF: 0.610 AC: 2937 AN: 4818

European-Finnish (FIN) AF: 0.692 AC: 7312 AN: 10562

Middle Eastern (MID) AF: 0.697 AC: 205 AN: 294

European-Non Finnish (NFE) AF: 0.723 AC: 49131 AN: 67962

Other (OTH) AF: 0.647 AC: 1367 AN: 2112

Alfa AF: 0.672 Hom.: 28884

Bravo AF: 0.583

Asia WGS AF: 0.472 AC: 1642 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

- -

Jun 16, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	8.4
DANN	Benign	0.69
PhyloP100		-0.087
PromoterAI		0.25	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2302762; hg19: chr17-7358861; COSMIC: COSV60142490; COSMIC: COSV60142490;