rs780673811

Variant names:

• chr17-7455302-C-T
• rs780673811
• NM_000747.3:c.1063C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PP3_Strong BP6

The NM_000747.3(CHRNB1):​c.1063C>T​(p.Pro355Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000211 in 1,614,000 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: CHRNB1 NM_000747.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 6.78

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.963
• BP6: Variant 17-7455302-C-T is Benign according to our data. Variant chr17-7455302-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 576409.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.1063C>T	p.Pro355Ser	missense_variant	Exon 9 of 11	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.1063C>T	p.Pro355Ser	missense_variant	Exon 9 of 11	1	NM_000747.3	ENSP00000304290.2

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000676 AC: 17 AN: 251474 AF XY: 0.0000441

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000924

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000212 AC: 31 AN: 1461858 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727224

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33476

Gnomad4 AMR exome AF: 0.00 AC: 0 AN: 44722

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26136

Gnomad4 EAS exome AF: 0.000680 AC: 27 AN: 39700

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 86254

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53416

Gnomad4 NFE exome AF: 0.00000270 AC: 3 AN: 1112000

Gnomad4 Remaining exome AF: 0.0000166 AC: 1 AN: 60388

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152142 Hom.: 0 Cov.: 30 AF XY: 0.0000404 AC XY: 3 AN XY: 74332

Gnomad4 AFR AF: 0.00 AC: 0 AN: 0

Gnomad4 AMR AF: 0.00 AC: 0 AN: 0

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.000577 AC: 0.000576923 AN: 0.000576923

Gnomad4 SAS AF: 0.00 AC: 0 AN: 0

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00 AC: 0 AN: 0

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000576 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Feb 24, 2023

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myasthenic syndrome 2A Benign:1

Dec 24, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.79
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.32
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D
MetaSVM	Uncertain	0.46	D
MutationAssessor	Pathogenic	3.2	M;.;.
PrimateAI	Uncertain	0.50	T
PROVEAN	Pathogenic	-7.8	D;D;.
REVEL	Pathogenic	0.67
Sift	Pathogenic	0.0	D;D;.
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;.;.
Vest4		0.74
MutPred		0.90		Loss of helix (P = 0.0167);.;.;
MVP		0.95
MPC		1.2
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.89
gMVP		0.90
Mutation Taster		=38/62	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs780673811; hg19: chr17-7358621;