rs76927517

chr17-7455835-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000747.3(CHRNB1):c.1259T>C(p.Ile420Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,098 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (17 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (21 hom.)
• Consequence: CHRNB1 NM_000747.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 2.04

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 (MetaRNN=0.00463894).
• BP6: Variant 17-7455835-T-C is Benign according to our data. Variant chr17-7455835-T-C is described in ClinVar as [Benign]. Clinvar id is 128751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00979 (1490/152208) while in subpopulation AFR AF= 0.0336 (1393/41518). AF 95% confidence interval is 0.0321. There are 17 homozygotes in gnomad4. There are 719 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 16 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNB1	NM_000747.3	c.1259T>C	p.Ile420Thr	missense_variant	10/11	ENST00000306071.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNB1	ENST00000306071.7	c.1259T>C	p.Ile420Thr	missense_variant	10/11	1	NM_000747.3	P1

Frequencies

GnomAD3 genomes AF: 0.00974 AC: 1481 AN: 152090 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00293 AC: 737 AN: 251464 Hom.: 11 AF XY: 0.00209 AC XY: 284 AN XY: 135908

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00118 AC: 1722 AN: 1461890 Hom.: 21 Cov.: 33 AF XY: 0.000974 AC XY: 708 AN XY: 727246

Gnomad4 AFR exome AF: 0.0342

Gnomad4 AMR exome AF: 0.00391

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000179

Gnomad4 OTH exome AF: 0.00290

GnomAD4 genome AF: 0.00979 AC: 1490 AN: 152208 Hom.: 17 Cov.: 31 AF XY: 0.00966 AC XY: 719 AN XY: 74412

Gnomad4 AFR AF: 0.0336

Gnomad4 AMR AF: 0.00445

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000206

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00218 Hom.: 9

Bravo AF: 0.0112

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00352 AC: 427

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Congenital myasthenic syndrome 2A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

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
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	19
Dann	Benign	0.95
DEOGEN2	Benign	0.18	T;.;.
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.0046	T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.57	N;.;.
MutationTaster	Benign	1.0	D;N;N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.64	N;N;.
REVEL	Benign	0.26
Sift	Benign	0.41	T;T;.
Sift4G	Benign	0.44	T;T;T
Polyphen		0.0020	B;.;.
Vest4		0.25
MVP		0.84
MPC		0.52
ClinPred		0.0044	T
GERP RS		3.4
Varity_R		0.18
gMVP		0.61

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: rs76927517; hg19: chr17-7359154;