chr17-4899365-G-A

Position:

• chr17-4899365-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PP3_Strong PP5

The NM_000080.4(CHRNE):​c.1052C>T​(p.Pro351Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000847 in 1,534,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000087 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:1
• Conservation: PhyloP100: 5.25

Genes affected

CHRNE (HGNC:1966): (cholinergic receptor nicotinic epsilon subunit) Acetylcholine receptors at mature mammalian neuromuscular junctions are pentameric protein complexes composed of four subunits in the ratio of two alpha subunits to one beta, one epsilon, and one delta subunit. The acetylcholine receptor changes subunit composition shortly after birth when the epsilon subunit replaces the gamma subunit seen in embryonic receptors. Mutations in the epsilon subunit are associated with congenital myasthenic syndrome. [provided by RefSeq, Sep 2009]

CHRNE (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 127) in uniprot entity ACHE_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000080.4
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.989
• PP5: Variant 17-4899365-G-A is Pathogenic according to our data. Variant chr17-4899365-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465851.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=1}. Variant chr17-4899365-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1052C>T	p.Pro351Leu	missense_variant	10/12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.1016C>T	p.Pro339Leu	missense_variant	11/13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1052C>T	p.Pro351Leu	missense_variant	10/12		NM_000080.4	ENSP00000497829.1
CHRNE	ENST00000649830.1	c.119C>T	p.Pro40Leu	missense_variant	10/11			ENSP00000496907.1
CHRNE	ENST00000572438.1	n.738C>T		non_coding_transcript_exon_variant	5/7	5
CHRNE	ENST00000652550.1	n.782C>T		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000868 AC: 12 AN: 1382156 Hom.: 0 Cov.: 35 AF XY: 0.0000132 AC XY: 9 AN XY: 682604

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000111

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152140 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74322

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

CHRNE-related disorder Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 29, 2023

The CHRNE c.1052C>T variant is predicted to result in the amino acid substitution p.Pro351Leu. This variant, described as p.Pro331Leu based on legacy nomenclature, was reported in the homozygous state in two affected siblings with congenital myasthenic syndrome (Croxen et al. 2001. PubMed ID: 11408331). In expression studies, the p.Pro351Leu substitution was reported to severely reduce surface expression of acetylcholine receptor (Croxen et al. 2001. PubMed ID: 11408331). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), although it should be noted that coverage of this region is absent in the gnomAD exome dataset and therefore allele frequency data may be not be accurate. This variant is interpreted as likely pathogenic. -

Congenital myasthenic syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jul 20, 2023

Variant summary: CHRNE c.1052C>T (p.Pro351Leu) results in a non-conservative amino acid change to a highly conserved residue (HGMD) located in the Neurotransmitter-gated ion-channel transmembrane domain (IPR006029) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 131104 control chromosomes (gnomAD). c.1052C>T has been reported in the literature in related homozygous individuals affected with Congenital Myasthenic Syndrome and AChR deficiency, showing evidence of cosegregation with disease in this family (Croxen_2001). These data indicate that the variant is likely to be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function, finding that HEK293 cells expressing the epsilon-subunit with the variant lack the ability to bind alpha-Bungarotoxin, and that the protein fails to incorporate into the surface AChR complex (Croxen_2001). The following publication has been ascertained in the context of this evaluation (PMID: 11408331). One submitter has cited a clinical-significance assessment for this variant to ClinVar after 2014 and has classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Congenital myasthenic syndrome 4A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 31, 2021

This sequence change replaces proline with leucine at codon 351 of the CHRNE protein (p.Pro351Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. This missense change has been observed in individual(s) with congenital myasthenic syndrome (CMS) (PMID: 11408331). It has also been observed to segregate with disease in related individuals. This variant is also known as c.992C>T; p.P331L. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects CHRNE function (PMID: 11408331). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.81	.;T;D
M_CAP	Pathogenic	0.82	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Pathogenic	4.2	H;H;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-8.6	D;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0020	D;.;.
Polyphen		1.0	D;D;.
Vest4		0.78
MutPred		0.88		Loss of loop (P = 0.0374);Loss of loop (P = 0.0374);.;
MVP		0.95
MPC		0.70
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.86
gMVP		0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1168592296; hg19: chr17-4802660;