rs79747991

Positions:

• chr17-7456741-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The ENST00000306071.7(CHRNB1):​c.*18C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00232 in 1,614,126 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0024 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0023 (5 hom.)
• Consequence: CHRNB1 ENST00000306071.7 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: -0.181

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-7456741-C-T is Benign according to our data. Variant chr17-7456741-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 256770.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00238 (362/152284) while in subpopulation NFE AF= 0.00382 (260/68026). AF 95% confidence interval is 0.00344. There are 1 homozygotes in gnomad4. There are 193 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.*18C>T		3_prime_UTR_variant	11/11	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.*18C>T		3_prime_UTR_variant	11/11	1	NM_000747.3	ENSP00000304290	P1
CHRNB1	ENST00000536404.6	c.*18C>T		3_prime_UTR_variant	10/10	2		ENSP00000439209
CHRNB1	ENST00000575379.1	c.*18C>T		3_prime_UTR_variant	2/2	2		ENSP00000461751
CHRNB1	ENST00000576360.1	c.*18C>T		3_prime_UTR_variant	10/10	3		ENSP00000459092

Frequencies

GnomAD3 genomes AF: 0.00237 AC: 361 AN: 152166 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00382

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00219 AC: 551 AN: 251384 Hom.: 1 AF XY: 0.00210 AC XY: 286 AN XY: 135890

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00171

Gnomad ASJ exome AF: 0.00536

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00310

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00232 AC: 3387 AN: 1461842 Hom.: 5 Cov.: 32 AF XY: 0.00234 AC XY: 1700 AN XY: 727226

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.00143

Gnomad4 ASJ exome AF: 0.00440

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000128

Gnomad4 FIN exome AF: 0.00303

Gnomad4 NFE exome AF: 0.00259

Gnomad4 OTH exome AF: 0.00205

GnomAD4 genome AF: 0.00238 AC: 362 AN: 152284 Hom.: 1 Cov.: 31 AF XY: 0.00259 AC XY: 193 AN XY: 74456

Gnomad4 AFR AF: 0.000241

Gnomad4 AMR AF: 0.00308

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.00382

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00344 Hom.: 0

Bravo AF: 0.00215

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Congenital myasthenic syndrome 4C Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 11, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.5
DANN	Benign	0.65

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

Publications

LitVar

Other links and lift over

dbSNP: rs79747991; hg19: chr17-7360060;