chr17-7446931-G-A

Variant names:

• chr17-7446931-G-A
• rs75019736
• NM_000747.3:c.342G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_000747.3(CHRNB1):​c.342G>A​(p.Val114Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00396 in 1,613,548 control chromosomes in the GnomAD database, including 26 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 0.0040 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (23 hom.)
• Consequence: CHRNB1 NM_000747.3 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.203
• Publications: 2 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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-7446931-G-A is Benign according to our data. Variant chr17-7446931-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 197164.
• BP7: Synonymous conserved (PhyloP=0.203 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00402 (612/152278) while in subpopulation AMR AF = 0.0103 (157/15304). AF 95% confidence interval is 0.00895. There are 3 homozygotes in GnomAd4. There are 335 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.342G>A	p.Val114Val	synonymous	Exon 4 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.342G>A	p.Val114Val	synonymous	Exon 4 of 11	ENSP00000304290.2
	CHRNB1	ENST00000536404.6	TSL:2	c.126G>A	p.Val42Val	synonymous	Exon 3 of 10	ENSP00000439209.2
	CHRNB1	ENST00000576360.1	TSL:3	c.126G>A	p.Val42Val	synonymous	Exon 3 of 10	ENSP00000459092.1

Frequencies

GnomAD3 genomes AF: 0.00402 AC: 612 AN: 152160 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00792

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00466

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00342 AC: 851 AN: 248710 AF XY: 0.00329

Gnomad AFR exome AF: 0.000566

Gnomad AMR exome AF: 0.00488

Gnomad ASJ exome AF: 0.00310

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00605

Gnomad NFE exome AF: 0.00430

Gnomad OTH exome AF: 0.00379

GnomAD4 exome AF: 0.00395 AC: 5778 AN: 1461270 Hom.: 23 Cov.: 33 AF XY: 0.00391 AC XY: 2844 AN XY: 726912

African (AFR) AF: 0.000538 AC: 18 AN: 33476

American (AMR) AF: 0.00510 AC: 228 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.00368 AC: 96 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000383 AC: 33 AN: 86220

European-Finnish (FIN) AF: 0.00672 AC: 357 AN: 53134

Middle Eastern (MID) AF: 0.00313 AC: 18 AN: 5758

European-Non Finnish (NFE) AF: 0.00435 AC: 4840 AN: 1111798

Other (OTH) AF: 0.00311 AC: 188 AN: 60378

GnomAD4 genome AF: 0.00402 AC: 612 AN: 152278 Hom.: 3 Cov.: 32 AF XY: 0.00450 AC XY: 335 AN XY: 74446

African (AFR) AF: 0.000818 AC: 34 AN: 41560

American (AMR) AF: 0.0103 AC: 157 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5172

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00792 AC: 84 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00465 AC: 316 AN: 68018

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00384 Hom.: 1

Bravo AF: 0.00365

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (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	-0.37
CADD	Benign	13
DANN	Benign	0.94
PhyloP100		0.20
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs75019736; hg19: chr17-7350250;