17-7445306-A-C

Variant names:

• chr17-7445306-A-C
• rs17856697
• NM_000747.3:c.95A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000747.3(CHRNB1):​c.95A>C​(p.Glu32Ala) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E32G) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNB1 NM_000747.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.06
• Publications: 27 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

ENSG00000272884 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25599366).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNB1	NM_000747.3	c.95A>C	p.Glu32Ala	missense_variant	Exon 2 of 11	ENST00000306071.7	NP_000738.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNB1	ENST00000306071.7	c.95A>C	p.Glu32Ala	missense_variant	Exon 2 of 11	1	NM_000747.3	ENSP00000304290.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 52

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 14866

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	23
DANN	Benign	0.95
DEOGEN2	Benign	0.28	T;.
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.3	L;.
PhyloP100		6.1
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-2.1	N;.
REVEL	Benign	0.28
Sift	Benign	0.65	T;.
Sift4G	Benign	0.53	T;T
Polyphen		0.41	B;.
Vest4		0.22
MutPred		0.33		Gain of MoRF binding (P = 0.0305);Gain of MoRF binding (P = 0.0305);
MVP		0.89
MPC		0.58
ClinPred		0.73	D
GERP RS		5.4
PromoterAI		0.042	Neutral
Varity_R		0.15
gMVP		0.51

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs17856697; hg19: chr17-7348625;