rs3855924

chr17-7457004-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000747.3(CHRNB1):c.*281T>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 0.165 in 455,056 control chromosomes in the GnomAD database, including 6,688 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.16 (2209 hom., cov: 32)
  • Exomes 𝑓: 0.17 (4479 hom.)
• Consequence: CHRNB1 NM_000747.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.741

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 17-7457004-T-C is Benign according to our data. Variant chr17-7457004-T-C is described in ClinVar as [Benign]. Clinvar id is 325112.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.202 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB1	NM_000747.3	c.*281T>C		3_prime_UTR_variant	11/11	ENST00000306071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB1	ENST00000306071.7	c.*281T>C		3_prime_UTR_variant	11/11	1	NM_000747.3	P1
CHRNB1	ENST00000575379.1	c.*281T>C		3_prime_UTR_variant	2/2	2
CHRNB1	ENST00000576360.1	c.*281T>C		3_prime_UTR_variant	10/10	3

Frequencies

GnomAD3 genomes AF: 0.163 AC: 24828 AN: 151992 Hom.: 2198 Cov.: 32

Gnomad AFR AF: 0.148

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.196

Gnomad SAS AF: 0.212

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.166 AC: 50407 AN: 302944 Hom.: 4479 Cov.: 3 AF XY: 0.168 AC XY: 27096 AN XY: 161652

Gnomad4 AFR exome AF: 0.137

Gnomad4 AMR exome AF: 0.208

Gnomad4 ASJ exome AF: 0.0984

Gnomad4 EAS exome AF: 0.199

Gnomad4 SAS exome AF: 0.211

Gnomad4 FIN exome AF: 0.239

Gnomad4 NFE exome AF: 0.149

Gnomad4 OTH exome AF: 0.161

GnomAD4 genome AF: 0.163 AC: 24858 AN: 152112 Hom.: 2209 Cov.: 32 AF XY: 0.169 AC XY: 12576 AN XY: 74346

Gnomad4 AFR AF: 0.148

Gnomad4 AMR AF: 0.197

Gnomad4 ASJ AF: 0.100

Gnomad4 EAS AF: 0.196

Gnomad4 SAS AF: 0.213

Gnomad4 FIN AF: 0.246

Gnomad4 NFE AF: 0.151

Gnomad4 OTH AF: 0.160

Alfa AF: 0.145 Hom.: 1695

Bravo AF: 0.157

Asia WGS AF: 0.269 AC: 934 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2018

- -

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	-0.83
Cadd	Benign	10
Dann	Benign	0.31

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

Publications

LitVar

Other links and lift over

dbSNP: rs3855924; hg19: chr17-7360323;