2-174753570-G-T

Variant names:

• chr2-174753570-G-T
• rs137852798
• NM_000079.4:c.711C>A

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PS1 PM2 PP2 PP3 PP5_Moderate

The NM_000079.4(CHRNA1):​c.711C>A​(p.Asn237Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. 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 (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N237I) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.94
• 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: Pathogenic. The variant received 10 ACMG points.

• PS1: Transcript NM_000079.4 (CHRNA1) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• 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, 0.828
• PP5: Variant 2-174753570-G-T is Pathogenic according to our data. Variant chr2-174753570-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 466184.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.711C>A	p.Asn237Lys	missense_variant	Exon 6 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.786C>A	p.Asn262Lys	missense_variant	Exon 7 of 10		NP_001034612.1
CHRNA1	XM_017003256.2	c.807C>A	p.Asn269Lys	missense_variant	Exon 6 of 9		XP_016858745.1
CHRNA1	XM_017003257.2	c.732C>A	p.Asn244Lys	missense_variant	Exon 5 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.711C>A	p.Asn237Lys	missense_variant	Exon 6 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Lethal multiple pterygium syndrome Pathogenic:1

Mar 19, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This missense change has been reported to affect CHRNA1 protein function (PMID: 8872460). For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. This missense change has been observed in individuals affected with autosomal dominant congenital myasthenic syndrome (PMID: 29395675, 8872460). This variant is also known as N217K in the literature. ClinVar contains an entry for this variant (Variation ID: 466184). This variant is not present in population databases (ExAC no frequency). This sequence change replaces asparagine with lysine at codon 237 of the CHRNA1 protein (p.Asn237Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Uncertain	0.051	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	8.8
DANN	Benign	0.95
DEOGEN2	Pathogenic	0.87	.;D;T;T;T;.
Eigen	Benign	-0.86
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.15	N
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Pathogenic	3.1	.;M;.;.;.;.
PhyloP100		-1.9
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-4.9	D;D;D;D;.;D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0050	D;D;D;D;.;D
Sift4G	Uncertain	0.0020	D;D;D;D;.;D
Polyphen		0.97, 1.0	.;D;.;.;.;D
Vest4		0.99
MutPred		0.86		.;Gain of methylation at N262 (P = 8e-04);.;.;.;.;
MVP		0.70
MPC		0.92
ClinPred		0.99	D
GERP RS		-8.2
Varity_R		0.85
gMVP		0.96
Mutation Taster		=0/100	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: rs137852798; hg19: chr2-175618298;