NM_000747.3:c.593A>C

Variant names:

• chr17-7447633-A-C
• rs76251791
• NM_000747.3:c.593A>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000747.3(CHRNB1):​c.593A>C​(p.His198Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H198R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNB1 NM_000747.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.09
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.593A>C	p.His198Pro	missense	Exon 6 of 11	NP_000738.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNB1	ENST00000306071.7	TSL:1 MANE Select	c.593A>C	p.His198Pro	missense	Exon 6 of 11	ENSP00000304290.2
	CHRNB1	ENST00000536404.6	TSL:2	c.377A>C	p.His126Pro	missense	Exon 5 of 10	ENSP00000439209.2
	CHRNB1	ENST00000576360.1	TSL:3	c.377A>C	p.His126Pro	missense	Exon 5 of 10	ENSP00000459092.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 2A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.064
Eigen_PC	Benign	0.094
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.060	D
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.90	L
PhyloP100		5.1
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.40
Sift	Uncertain	0.0070	D
Sift4G	Benign	0.081	T
Polyphen		0.0040	B
Vest4		0.52
MutPred		0.60		Gain of disorder (P = 0.0918)
MVP		0.91
MPC		0.64
ClinPred		0.61	D
GERP RS		5.0
Varity_R		0.43
gMVP		0.77

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: rs76251791; hg19: chr17-7350952;