17-4899365-G-C

Variant names:

• chr17-4899365-G-C
• rs1168592296
• NM_000080.4:c.1052C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_000080.4(CHRNE):​c.1052C>G​(p.Pro351Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000289 in 1,382,156 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 Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P351L) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.25
• Publications: 0 publications found

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]

C17orf107 (HGNC:37238): (chromosome 17 open reading frame 107)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-4899365-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 465851.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.966
• PP5: Variant 17-4899365-G-C is Pathogenic according to our data. Variant chr17-4899365-G-C is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2577839.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1052C>G	p.Pro351Arg	missense_variant	Exon 10 of 12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.-398G>C		upstream_gene_variant		ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1052C>G	p.Pro351Arg	missense_variant	Exon 10 of 12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.-398G>C		upstream_gene_variant		2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1382156 Hom.: 0 Cov.: 35 AF XY: 0.00000439 AC XY: 3 AN XY: 682604

African (AFR) AF: 0.00 AC: 0 AN: 31266

American (AMR) AF: 0.00 AC: 0 AN: 33680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24360

East Asian (EAS) AF: 0.00 AC: 0 AN: 35962

South Asian (SAS) AF: 0.00 AC: 0 AN: 78956

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37868

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4758

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1077852

Other (OTH) AF: 0.00 AC: 0 AN: 57454

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A Pathogenic:1

Aug 29, 2023

Concord Molecular Medicine Laboratory, Concord Repatriation General Hospital

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1052C>G missense substitution predicts an amino acid change from from proline to arginine in codon 351 of the CHRNE protein, p.(Pro351Arg). This variant is detected in a compound heterozygous state with another likely pathogenic CHRNE variant (phase not confirmed) in a patient with a clinical diagnosis of congenital myasthenic syndrome. In silico analysis by REVEL suggests this variant to be damaging (REVEL: 0.77). It is located in the critical neurotransmitter-gated ion-channel transmembrane domain (IPR006029). Another amino acid change in the same residue location has been observed in a patient with CMS in trans with another pathogenic variant (PMID: 11408331). This variant is absent in control population (gnomAD). The current evidence allows a classification of this variant as “likely pathogenic” (ACMG criteria: PM1, PM5, PP3_moderate, PM2_supporting, PM3_supporting).

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	D;D;.
Eigen	Pathogenic	0.81
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.0	.;T;T
M_CAP	Pathogenic	0.80	D
MetaRNN	Pathogenic	0.97	D;D;D
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	4.2	H;H;.
PhyloP100		5.3
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-7.9	D;.;.
REVEL	Pathogenic	0.77
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;.;.
Vest4		0.66
ClinPred		1.0	D
GERP RS		4.9
PromoterAI		0.047	Neutral
Varity_R		0.89
gMVP		0.84
Mutation Taster		=34/66	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: rs1168592296; hg19: chr17-4802660; COSMIC: COSV53417628; COSMIC: COSV53417628;