17-7456791-T-C

Position:

• chr17-7456791-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.*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

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=-0.84).
• BP6: Variant 17-7456791-T-C is Benign according to our data. Variant chr17-7456791-T-C is described in ClinVar as [Benign]. Clinvar id 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/exons	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.*68T>C		3_prime_UTR_variant	11/11	ENST00000306071.7	NP_000738.2

Ensembl

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

Gnomad4 AFR exome AF: 0.106

Gnomad4 AMR exome AF: 0.425

Gnomad4 ASJ exome AF: 0.204

Gnomad4 EAS exome AF: 0.614

Gnomad4 SAS exome AF: 0.320

Gnomad4 FIN exome AF: 0.180

Gnomad4 NFE exome AF: 0.158

Gnomad4 OTH exome AF: 0.200

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

Gnomad4 AFR AF: 0.108

Gnomad4 AMR AF: 0.298

Gnomad4 ASJ AF: 0.214

Gnomad4 EAS AF: 0.616

Gnomad4 SAS AF: 0.330

Gnomad4 FIN AF: 0.185

Gnomad4 NFE AF: 0.162

Gnomad4 OTH AF: 0.178

Alfa AF: 0.177 Hom.: 4133

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.84
CADD	Benign	3.7
DANN	Benign	0.63

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: rs2302764; hg19: chr17-7360110; COSMIC: COSV60139685; COSMIC: COSV60139685;