2-174757645-G-A

Variant names:

• chr2-174757645-G-A
• rs912456299
• NM_000079.4:c.265C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000079.4(CHRNA1):​c.265C>T​(p.Pro89Ser) variant causes a missense change involving the alteration of a 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P89A) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNA1 NM_000079.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.91
• Publications: 0 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 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNA1	NM_000079.4	c.265C>T	p.Pro89Ser	missense_variant	Exon 4 of 9	ENST00000348749.9	NP_000070.1
CHRNA1	NM_001039523.3	c.340C>T	p.Pro114Ser	missense_variant	Exon 5 of 10		NP_001034612.1
CHRNA1	XM_017003256.2	c.361C>T	p.Pro121Ser	missense_variant	Exon 4 of 9		XP_016858745.1
CHRNA1	XM_017003257.2	c.286C>T	p.Pro96Ser	missense_variant	Exon 3 of 8		XP_016858746.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNA1	ENST00000348749.9	c.265C>T	p.Pro89Ser	missense_variant	Exon 4 of 9	1	NM_000079.4	ENSP00000261008.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

May 10, 2021

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.85
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	.;D;T;T;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.92
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.7	.;M;.;.;.
PhyloP100		9.9
PrimateAI	Uncertain	0.55	T
PROVEAN	Pathogenic	-7.5	D;D;D;.;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.016	D;D;D;.;D
Sift4G	Benign	0.091	T;T;T;.;D
Polyphen		0.94, 0.98	.;P;.;.;D
Vest4		0.90
MutPred		0.74		.;Loss of catalytic residue at P114 (P = 0.0558);.;.;.;
MVP		0.89
MPC		0.38
ClinPred		1.0	D
GERP RS		5.9
Varity_R		0.87
gMVP		0.71
Mutation Taster		=5/95	disease causing

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: rs912456299; hg19: chr2-175622373; COSMIC: COSV53684424;