rs137852805

Variant names:

• chr2-174753524-A-C
• rs137852805
• NM_000079.4:c.757T>G

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_000079.4(CHRNA1):​c.757T>G​(p.Phe253Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.27
• Publications: 3 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 11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_000079.4
• 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, 0.991
• PP5: Variant 2-174753524-A-C is Pathogenic according to our data. Variant chr2-174753524-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18383.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.757T>G	p.Phe253Val	missense_variant	Exon 6 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.832T>G	p.Phe278Val	missense_variant	Exon 7 of 10		NP_001034612.1
CHRNA1	XM_017003256.2	c.853T>G	p.Phe285Val	missense_variant	Exon 6 of 9		XP_016858745.1
CHRNA1	XM_017003257.2	c.778T>G	p.Phe260Val	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.757T>G	p.Phe253Val	missense_variant	Exon 6 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251122 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727234

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000106 Hom.: 0

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Myasthenic syndrome, congenital, 1B, fast-channel Pathogenic:1

Mar 01, 1999

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Lethal multiple pterygium syndrome Pathogenic:1

Jan 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces phenylalanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 253 of the CHRNA1 protein (p.Phe253Val). This variant is present in population databases (rs137852805, gnomAD 0.006%). This missense change has been observed in individual(s) with autosomal recessive congenital myasthenic syndrome (PMID: 10195214). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 18383). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt CHRNA1 protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects CHRNA1 function (PMID: 10195214). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.95	.;D;D;D;T;.
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D
M_CAP	Pathogenic	0.75	D
MetaRNN	Pathogenic	0.99	D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.5	.;M;.;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.6	D;D;D;D;.;D
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;D;D;D;.;D
Sift4G	Pathogenic	0.0010	D;D;D;D;.;D
Polyphen		0.78, 1.0	.;P;.;.;.;D
Vest4		0.98
MutPred		0.96		.;Gain of disorder (P = 0.1626);.;.;.;.;
MVP		0.99
MPC		0.99
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.98
gMVP		0.95
Mutation Taster		=2/98	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: rs137852805; hg19: chr2-175618252;