17-7454288-C-T

Variant names:

• chr17-7454288-C-T
• rs76001008
• NM_000747.3:c.821-9C>T

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.821-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0181 in 1,605,916 control chromosomes in the GnomAD database, including 321 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (26 hom., cov: 30)
  • Exomes 𝑓: 0.019 (295 hom.)
• Consequence: CHRNB1 NM_000747.3 intron
• Scores: Splicing: ADA: 0.00002066
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.925
• Publications: 3 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: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Ambry Genetics
• congenital myasthenic syndrome 2A

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, 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=-0.7).
• BP6: Variant 17-7454288-C-T is Benign according to our data. Variant chr17-7454288-C-T is described in ClinVar as Benign. ClinVar VariationId is 128753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0137 (2088/152276) while in subpopulation NFE AF = 0.0211 (1436/68014). AF 95% confidence interval is 0.0202. There are 26 homozygotes in GnomAd4. There are 963 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 26 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB1	NM_000747.3	MANE Select	c.821-9C>T		intron	N/A	NP_000738.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB1	ENST00000306071.7	TSL:1 MANE Select	c.821-9C>T		intron	N/A	ENSP00000304290.2	P11230-1
	CHRNB1	ENST00000536404.6	TSL:2	c.605-9C>T		intron	N/A	ENSP00000439209.2	P11230-2
	CHRNB1	ENST00000576360.1	TSL:3	c.605-156C>T		intron	N/A	ENSP00000459092.1	I3L1T7

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2087 AN: 152158 Hom.: 26 Cov.: 30

Gnomad AFR AF: 0.00372

Gnomad AMI AF: 0.0473

Gnomad AMR AF: 0.00851

Gnomad ASJ AF: 0.0452

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00904

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0211

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0147 AC: 3684 AN: 251452 AF XY: 0.0150

Gnomad AFR exome AF: 0.00246

Gnomad AMR exome AF: 0.00743

Gnomad ASJ exome AF: 0.0399

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0111

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0199

GnomAD4 exome AF: 0.0185 AC: 26935 AN: 1453640 Hom.: 295 Cov.: 31 AF XY: 0.0184 AC XY: 13324 AN XY: 723748

African (AFR) AF: 0.00270 AC: 90 AN: 33324

American (AMR) AF: 0.00805 AC: 360 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.0412 AC: 1075 AN: 26078

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39666

South Asian (SAS) AF: 0.00495 AC: 426 AN: 86106

European-Finnish (FIN) AF: 0.0119 AC: 635 AN: 53392

Middle Eastern (MID) AF: 0.0113 AC: 65 AN: 5754

European-Non Finnish (NFE) AF: 0.0210 AC: 23241 AN: 1104510

Other (OTH) AF: 0.0173 AC: 1040 AN: 60098

GnomAD4 genome AF: 0.0137 AC: 2088 AN: 152276 Hom.: 26 Cov.: 30 AF XY: 0.0129 AC XY: 963 AN XY: 74456

African (AFR) AF: 0.00371 AC: 154 AN: 41552

American (AMR) AF: 0.00850 AC: 130 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0452 AC: 157 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00643 AC: 31 AN: 4824

European-Finnish (FIN) AF: 0.00904 AC: 96 AN: 10618

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0211 AC: 1436 AN: 68014

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0201 Hom.: 28

Bravo AF: 0.0138

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0237

EpiControl AF: 0.0220

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		0.93
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.014
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

Other links and lift over

dbSNP: rs76001008; hg19: chr17-7357607;