17-7445183-C-A

Position:

chr17-7445183-C-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000747.3(CHRNB1):c.56C>A(p.Pro19Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000559 in 1,610,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

CHRNB1
NM_000747.3 missense, splice_region

Scores

Splicing: ADA: 0.001070

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.08

Variant links:

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 links:

ENSG00000272884 (HGNC:):

ENSG00000272884 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.10478285).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB1	NM_000747.3 link	c.56C>A	p.Pro19Gln	missense_variant, splice_region_variant	1/11	ENST00000306071.7	NP_000738.2	P11230-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CHRNB1	ENST00000306071.7 link	c.56C>A	p.Pro19Gln	missense_variant, splice_region_variant	1/11	1	NM_000747.3	ENSP00000304290.2	P11230-1
ENSG00000272884	ENST00000575331.1 link	n.4770C>A		non_coding_transcript_exon_variant	3/3	1
CHRNB1	ENST00000572857.5 link	c.56C>A	p.Pro19Gln	missense_variant, splice_region_variant	1/6	4		ENSP00000461402.1	I3L4N5
CHRNB1	ENST00000574054.1 link	n.76C>A		splice_region_variant, non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000850

AC:

AN:

235276

Hom.:

AF XY:

0.0000154

AC XY:

AN XY:

129730

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000193

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000480

AC:

AN:

1458380

Hom.:

Cov.:

AF XY:

0.00000551

AC XY:

AN XY:

725506

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000630

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152164

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74340

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000282

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000829

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 2A

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 27, 2022

This sequence change replaces proline, which is neutral and non-polar, with glutamine, which is neutral and polar, at codon 19 of the CHRNB1 protein (p.Pro19Gln). This variant is present in population databases (rs759176796, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with CHRNB1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1506790). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.089

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.076

T;.

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.21

M_CAP

Benign

0.035

MetaRNN

Benign

0.10

T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.4

L;.

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.11

Sift

Benign

0.61

T;.

Sift4G

Benign

0.31

T;T

Polyphen

0.0040

B;.

Vest4

0.34

MutPred

0.33

Loss of loop (P = 0.0073);Loss of loop (P = 0.0073);

MVP

0.82

MPC

0.37

ClinPred

0.17

GERP RS

2.6

Varity_R

0.056

gMVP

0.55

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0011

dbscSNV1_RF

Benign

0.040

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over