17-7456791-T-C

Variant names:

• chr17-7456791-T-C
• rs2302764
• NM_000747.3:c.*68T>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.*68T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,593,962 control chromosomes in the GnomAD database, including 36,723 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (3465 hom., cov: 32)
  • Exomes 𝑓: 0.19 (33258 hom.)
• Consequence: CHRNB1 NM_000747.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.19
• Publications: 22 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 17-7456791-T-C is Benign according to our data. Variant chr17-7456791-T-C is described in ClinVar as Benign. ClinVar VariationId is 325109.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.*68T>C		3_prime_UTR_variant	Exon 11 of 11	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.*68T>C		3_prime_UTR_variant	Exon 11 of 11	1	NM_000747.3	ENSP00000304290.2
CHRNB1	ENST00000536404.6	c.*68T>C		3_prime_UTR_variant	Exon 10 of 10	2		ENSP00000439209.2
CHRNB1	ENST00000576360.1	c.*68T>C		3_prime_UTR_variant	Exon 10 of 10	3		ENSP00000459092.1
CHRNB1	ENST00000575379.1	c.*68T>C		3_prime_UTR_variant	Exon 2 of 2	2		ENSP00000461751.1

Frequencies

GnomAD3 genomes AF: 0.184 AC: 27993 AN: 152034 Hom.: 3471 Cov.: 32

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.0855

Gnomad AMR AF: 0.298

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.616

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.215

Gnomad NFE AF: 0.162

Gnomad OTH AF: 0.179

GnomAD4 exome AF: 0.190 AC: 274637 AN: 1441810 Hom.: 33258 Cov.: 26 AF XY: 0.194 AC XY: 139470 AN XY: 718240

African (AFR) AF: 0.106 AC: 3507 AN: 33046

American (AMR) AF: 0.425 AC: 18840 AN: 44286

Ashkenazi Jewish (ASJ) AF: 0.204 AC: 5287 AN: 25944

East Asian (EAS) AF: 0.614 AC: 24264 AN: 39522

South Asian (SAS) AF: 0.320 AC: 27439 AN: 85720

European-Finnish (FIN) AF: 0.180 AC: 9430 AN: 52478

Middle Eastern (MID) AF: 0.197 AC: 1126 AN: 5724

European-Non Finnish (NFE) AF: 0.158 AC: 172807 AN: 1095312

Other (OTH) AF: 0.200 AC: 11937 AN: 59778

GnomAD4 genome AF: 0.184 AC: 27993 AN: 152152 Hom.: 3465 Cov.: 32 AF XY: 0.193 AC XY: 14378 AN XY: 74380

African (AFR) AF: 0.108 AC: 4472 AN: 41540

American (AMR) AF: 0.298 AC: 4554 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3470

East Asian (EAS) AF: 0.616 AC: 3171 AN: 5148

South Asian (SAS) AF: 0.330 AC: 1594 AN: 4826

European-Finnish (FIN) AF: 0.185 AC: 1965 AN: 10602

Middle Eastern (MID) AF: 0.204 AC: 60 AN: 294

European-Non Finnish (NFE) AF: 0.162 AC: 10981 AN: 67976

Other (OTH) AF: 0.178 AC: 376 AN: 2112

Alfa AF: 0.178 Hom.: 10375

Bravo AF: 0.189

Asia WGS AF: 0.425 AC: 1477 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

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	-0.84
CADD	Benign	3.7
DANN	Benign	0.63
PhyloP100		-1.2
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: rs2302764; hg19: chr17-7360110; COSMIC: COSV60139685; COSMIC: COSV60139685;