rs12452047

Variant names:

• chr17-7448517-A-G
• rs12452047
• NM_000747.3:c.611-62A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000747.3(CHRNB1):​c.611-62A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.159 in 1,539,548 control chromosomes in the GnomAD database, including 20,402 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.17 (2347 hom., cov: 31)
  • Exomes 𝑓: 0.16 (18055 hom.)
• Consequence: CHRNB1 NM_000747.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.162
• Publications: 7 publications found

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 2C

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• congenital myasthenic syndrome 1A

  Inheritance: AD Classification: STRONG Submitted by: PanelApp Australia
• congenital myasthenic syndrome 2A

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Ambry Genetics
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000308645 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 17-7448517-A-G is Benign according to our data. Variant chr17-7448517-A-G is described in ClinVar as Benign. ClinVar VariationId is 1262506.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.206 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.611-62A>G		intron_variant	Intron 6 of 10	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.611-62A>G		intron_variant	Intron 6 of 10	1	NM_000747.3	ENSP00000304290.2

Frequencies

GnomAD3 genomes AF: 0.168 AC: 25612 AN: 152062 Hom.: 2340 Cov.: 31

Gnomad AFR AF: 0.166

Gnomad AMI AF: 0.145

Gnomad AMR AF: 0.197

Gnomad ASJ AF: 0.100

Gnomad EAS AF: 0.195

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.245

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.151

Gnomad OTH AF: 0.153

GnomAD4 exome AF: 0.158 AC: 218672 AN: 1387366 Hom.: 18055 AF XY: 0.159 AC XY: 109968 AN XY: 693214

African (AFR) AF: 0.161 AC: 5136 AN: 31900

American (AMR) AF: 0.207 AC: 8995 AN: 43350

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 2551 AN: 25480

East Asian (EAS) AF: 0.201 AC: 7883 AN: 39160

South Asian (SAS) AF: 0.216 AC: 18014 AN: 83502

European-Finnish (FIN) AF: 0.238 AC: 12508 AN: 52606

Middle Eastern (MID) AF: 0.0814 AC: 410 AN: 5036

European-Non Finnish (NFE) AF: 0.147 AC: 153934 AN: 1048492

Other (OTH) AF: 0.160 AC: 9241 AN: 57840

GnomAD4 genome AF: 0.169 AC: 25650 AN: 152182 Hom.: 2347 Cov.: 31 AF XY: 0.174 AC XY: 12962 AN XY: 74396

African (AFR) AF: 0.166 AC: 6894 AN: 41528

American (AMR) AF: 0.198 AC: 3026 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.100 AC: 347 AN: 3470

East Asian (EAS) AF: 0.195 AC: 1008 AN: 5166

South Asian (SAS) AF: 0.217 AC: 1045 AN: 4826

European-Finnish (FIN) AF: 0.245 AC: 2594 AN: 10586

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.151 AC: 10239 AN: 67994

Other (OTH) AF: 0.160 AC: 339 AN: 2114

Alfa AF: 0.148 Hom.: 2207

Bravo AF: 0.162

Asia WGS AF: 0.270 AC: 936 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.8
DANN	Benign	0.84
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12452047; hg19: chr17-7351836;