chr17-4899337-G-GGGC

Position:

• chr17-4899337-G-GGGC

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PM4_Supporting

The NM_000080.4(CHRNE):​c.1077_1079dupGCC​(p.Pro360dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00039 in 1,547,780 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00054 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00037 (0 hom.)
• Consequence: CHRNE NM_000080.4 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.170

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 Uncertain_significance. Variant got 3 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
• PM4: Nonframeshift variant in NON repetitive region in NM_000080.4. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1077_1079dupGCC	p.Pro360dup	disruptive_inframe_insertion	10/12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.1041_1043dupGCC	p.Pro348dup	disruptive_inframe_insertion	11/13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1077_1079dupGCC	p.Pro360dup	disruptive_inframe_insertion	10/12		NM_000080.4	ENSP00000497829.1
CHRNE	ENST00000649830.1	c.144_146dupGCC	p.Pro49dup	disruptive_inframe_insertion	10/11			ENSP00000496907.1
CHRNE	ENST00000572438.1	n.763_765dupGCC		non_coding_transcript_exon_variant	5/7	5
CHRNE	ENST00000652550.1	n.807_809dupGCC		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.000527 AC: 80 AN: 151852 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.0286

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000778

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000515

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000361 AC: 53 AN: 146728 Hom.: 0 AF XY: 0.000368 AC XY: 30 AN XY: 81598

Gnomad AFR exome AF: 0.000270

Gnomad AMR exome AF: 0.000208

Gnomad ASJ exome AF: 0.00100

Gnomad EAS exome AF: 0.000355

Gnomad SAS exome AF: 0.000378

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000407

Gnomad OTH exome AF: 0.000237

GnomAD4 exome AF: 0.000373 AC: 521 AN: 1395812 Hom.: 0 Cov.: 35 AF XY: 0.000392 AC XY: 271 AN XY: 690526

Gnomad4 AFR exome AF: 0.000189

Gnomad4 AMR exome AF: 0.000168

Gnomad4 ASJ exome AF: 0.00136

Gnomad4 EAS exome AF: 0.000275

Gnomad4 SAS exome AF: 0.000446

Gnomad4 FIN exome AF: 0.0000265

Gnomad4 NFE exome AF: 0.000358

Gnomad4 OTH exome AF: 0.000637

GnomAD4 genome AF: 0.000540 AC: 82 AN: 151968 Hom.: 0 Cov.: 32 AF XY: 0.000619 AC XY: 46 AN XY: 74294

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000780

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000515

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000699

Asia WGS AF: 0.00115 AC: 4 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 10, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Apr 23, 2024	In-frame insertion of 1 amino acids in a non-repeat region; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 13, 2015	- -

Congenital myasthenic syndrome 4A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 13, 2022

This variant, c.1077_1079dup, results in the insertion of 1 amino acid(s) of the CHRNE protein (p.Pro360dup), but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs752226476, gnomAD 0.1%). This variant has not been reported in the literature in individuals affected with CHRNE-related conditions. ClinVar contains an entry for this variant (Variation ID: 465852). 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. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Jul 28, 2021

- -

Congenital myasthenic syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Jan 17, 2020

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs752226476; hg19: chr17-4802632;