rs79209506

Variant names:

• chr17-7455278-C-G
• rs79209506
• NM_000747.3:c.1045-6C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000747.3(CHRNB1):​c.1045-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00488 in 1,614,028 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (5 hom., cov: 30)
  • Exomes 𝑓: 0.0050 (27 hom.)
• Consequence: CHRNB1 NM_000747.3 splice_region, intron
• Scores: Splicing: ADA: 0.005259
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.284
• Publications: 1 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=-0.73).
• BP6: Variant 17-7455278-C-G is Benign according to our data. Variant chr17-7455278-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 199037.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00399 (608/152296) while in subpopulation AMR AF = 0.00791 (121/15296). AF 95% confidence interval is 0.00677. There are 5 homozygotes in GnomAd4. There are 292 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000747.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB1	NM_000747.3	MANE Select	c.1045-6C>G		splice_region intron	N/A	NP_000738.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB1	ENST00000306071.7	TSL:1 MANE Select	c.1045-6C>G		splice_region intron	N/A	ENSP00000304290.2
	ENSG00000308645	ENST00000835515.1		n.215G>C		non_coding_transcript_exon	Exon 1 of 2
	CHRNB1	ENST00000536404.6	TSL:2	c.829-6C>G		splice_region intron	N/A	ENSP00000439209.2

Frequencies

GnomAD3 genomes AF: 0.00400 AC: 608 AN: 152178 Hom.: 5 Cov.: 30

Gnomad AFR AF: 0.00140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00565

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00398 AC: 1001 AN: 251416 AF XY: 0.00386

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00483

Gnomad ASJ exome AF: 0.00248

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00594

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.00497 AC: 7270 AN: 1461732 Hom.: 27 Cov.: 32 AF XY: 0.00481 AC XY: 3499 AN XY: 727174

African (AFR) AF: 0.000777 AC: 26 AN: 33472

American (AMR) AF: 0.00463 AC: 207 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00279 AC: 73 AN: 26132

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.00230 AC: 198 AN: 86248

European-Finnish (FIN) AF: 0.00114 AC: 61 AN: 53408

Middle Eastern (MID) AF: 0.00261 AC: 15 AN: 5752

European-Non Finnish (NFE) AF: 0.00579 AC: 6438 AN: 1111918

Other (OTH) AF: 0.00416 AC: 251 AN: 60386

GnomAD4 genome AF: 0.00399 AC: 608 AN: 152296 Hom.: 5 Cov.: 30 AF XY: 0.00392 AC XY: 292 AN XY: 74474

African (AFR) AF: 0.00140 AC: 58 AN: 41562

American (AMR) AF: 0.00791 AC: 121 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00563 AC: 383 AN: 68016

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00450 Hom.: 1

Bravo AF: 0.00440

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00698

EpiControl AF: 0.00628

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Congenital myasthenic syndrome 2A (1)
-	-	1	Congenital myasthenic syndrome 4C (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	11
DANN	Benign	0.69
PhyloP100		0.28
PromoterAI		-0.040	Neutral
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0053
dbscSNV1_RF	Benign	0.12
SpliceAI score (max)		0.060		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: rs79209506; hg19: chr17-7358597; COSMIC: COSV107325813; COSMIC: COSV107325813;