chr17-7455835-T-C

Variant names:

• chr17-7455835-T-C
• rs76927517
• NM_000747.3:c.1259T>C

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.1259T>C​(p.Ile420Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,614,098 control chromosomes in the GnomAD database, including 38 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0098 (17 hom., cov: 31)
  • Exomes 𝑓: 0.0012 (21 hom.)
• Consequence: CHRNB1 NM_000747.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.04
• 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: 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.00463894).
• BP6: Variant 17-7455835-T-C is Benign according to our data. Variant chr17-7455835-T-C is described in ClinVar as Benign. ClinVar VariationId is 128751.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00979 (1490/152208) while in subpopulation AFR AF = 0.0336 (1393/41518). AF 95% confidence interval is 0.0321. There are 17 homozygotes in GnomAd4. There are 719 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AD,AR 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.1259T>C	p.Ile420Thr	missense	Exon 10 of 11	NP_000738.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB1	ENST00000306071.7	TSL:1 MANE Select	c.1259T>C	p.Ile420Thr	missense	Exon 10 of 11	ENSP00000304290.2	P11230-1
	CHRNB1	ENST00000536404.6	TSL:2	c.1043T>C	p.Ile348Thr	missense	Exon 9 of 10	ENSP00000439209.2	P11230-2
	CHRNB1	ENST00000576360.1	TSL:3	c.896T>C	p.Ile299Thr	missense	Exon 9 of 10	ENSP00000459092.1	I3L1T7

Frequencies

GnomAD3 genomes AF: 0.00974 AC: 1481 AN: 152090 Hom.: 16 Cov.: 31

Gnomad AFR AF: 0.0334

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00293 AC: 737 AN: 251464 AF XY: 0.00209

Gnomad AFR exome AF: 0.0353

Gnomad AMR exome AF: 0.00356

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00118 AC: 1722 AN: 1461890 Hom.: 21 Cov.: 33 AF XY: 0.000974 AC XY: 708 AN XY: 727246

African (AFR) AF: 0.0342 AC: 1144 AN: 33480

American (AMR) AF: 0.00391 AC: 175 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00451 AC: 26 AN: 5768

European-Non Finnish (NFE) AF: 0.000179 AC: 199 AN: 1112008

Other (OTH) AF: 0.00290 AC: 175 AN: 60396

GnomAD4 genome AF: 0.00979 AC: 1490 AN: 152208 Hom.: 17 Cov.: 31 AF XY: 0.00966 AC XY: 719 AN XY: 74412

African (AFR) AF: 0.0336 AC: 1393 AN: 41518

American (AMR) AF: 0.00445 AC: 68 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68022

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00274 Hom.: 11

Bravo AF: 0.0112

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0352 AC: 155

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00352 AC: 427

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000296

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
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.33
FATHMM_MKL	Uncertain	0.81	D
MetaRNN	Benign	0.0046	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.57	N
PhyloP100		2.0
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.64	N
REVEL	Benign	0.26
Sift	Benign	0.41	T
Sift4G	Benign	0.44	T
Polyphen		0.0020	B
Vest4		0.25
MVP		0.84
MPC		0.52
ClinPred		0.0044	T
GERP RS		3.4
PromoterAI		0.057	Neutral
Varity_R		0.18
gMVP		0.61
Mutation Taster		=91/9	polymorphism

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: rs76927517; hg19: chr17-7359154;