rs137852802

Variant names:

• chr2-174750082-C-A
• rs137852802
• NM_000079.4:c.866G>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP2 PP3_Moderate PP5

The NM_000079.4(CHRNA1):​c.866G>T​(p.Ser289Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 4.79
• Publications: 5 publications found

Genes affected

CHRNA1 (HGNC:1955): (cholinergic receptor nicotinic alpha 1 subunit) The muscle acetylcholine receptor consiststs of 5 subunits of 4 different types: 2 alpha subunits and 1 each of the beta, gamma, and delta subunits. This gene encodes an alpha subunit that plays a role in acetlycholine binding/channel gating. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Nov 2012]

CHRNA1 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome 1A

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• lethal multiple pterygium syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, G2P
• myasthenic syndrome, congenital, 1B, fast-channel

  Inheritance: AR, AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000236449 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: 0.72157 (below the threshold of 3.09). Trascript score misZ: 1.6771 (below the threshold of 3.09). GenCC associations: The gene is linked to lethal multiple pterygium syndrome, congenital myasthenic syndrome 1A, myasthenic syndrome, congenital, 1B, fast-channel, postsynaptic congenital myasthenic syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.869
• PP5: Variant 2-174750082-C-A is Pathogenic according to our data. Variant chr2-174750082-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 18380.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.866G>T	p.Ser289Ile	missense_variant	Exon 7 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.941G>T	p.Ser314Ile	missense_variant	Exon 8 of 10		NP_001034612.1
CHRNA1	XM_017003256.2	c.962G>T	p.Ser321Ile	missense_variant	Exon 7 of 9		XP_016858745.1
CHRNA1	XM_017003257.2	c.887G>T	p.Ser296Ile	missense_variant	Exon 6 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.866G>T	p.Ser289Ile	missense_variant	Exon 7 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital myasthenic syndrome 1A Pathogenic:1

May 01, 1997

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.63
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.27
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.34	.;T;T;T;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.93	D;D;D;D;D
M_CAP	Benign	0.061	D
MetaRNN	Pathogenic	0.87	D;D;D;D;D
MetaSVM	Uncertain	0.32	D
MutationAssessor	Benign	1.4	.;L;.;.;.
PhyloP100		4.8
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	1.3	N;N;N;N;.
REVEL	Uncertain	0.59
Sift	Benign	0.094	T;T;T;T;.
Sift4G	Benign	0.14	T;T;T;T;.
Polyphen		0.95	.;P;.;.;.
Vest4		0.69
MutPred		0.76		.;Loss of disorder (P = 0.0734);.;.;.;
MVP		0.97
MPC		0.53
ClinPred		0.88	D
GERP RS		5.5
Varity_R		0.51
gMVP		0.79
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs137852802; hg19: chr2-175614810;