rs773526895

Variant names:

• chr17-4898864-T-TC
• rs773526895
• NM_000080.4:c.1353dupG

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_Strong PP5_Very_Strong

The NM_000080.4(CHRNE):​c.1353dupG​(p.Asn452GlufsTer4) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000781 in 1,587,524 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000080 (0 hom.)
• Consequence: CHRNE NM_000080.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:10 O:1
• Conservation: PhyloP100: -0.655
• Publications: 5 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]

CHRNE Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 12 pathogenic variants in the truncated region.
• PP5: Variant 17-4898864-T-TC is Pathogenic according to our data. Variant chr17-4898864-T-TC is described in ClinVar as Pathogenic. ClinVar VariationId is 243032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.1353dupG	p.Asn452GlufsTer4	frameshift	Exon 12 of 12	NP_000071.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1353dupG	p.Asn452GlufsTer4	frameshift	Exon 12 of 12	ENSP00000497829.1
	CHRNE	ENST00000649830.1		c.529dupG	p.Glu177GlyfsTer56	frameshift	Exon 11 of 11	ENSP00000496907.1
	CHRNE	ENST00000572438.1	TSL:5	n.1039dupG		non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152048 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

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

GnomAD2 exomes AF: 0.000148 AC: 30 AN: 202640 AF XY: 0.000193

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000712

Gnomad ASJ exome AF: 0.00265

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000450

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000801 AC: 115 AN: 1435476 Hom.: 0 Cov.: 34 AF XY: 0.0000857 AC XY: 61 AN XY: 711552

African (AFR) AF: 0.00 AC: 0 AN: 33174

American (AMR) AF: 0.0000510 AC: 2 AN: 39230

Ashkenazi Jewish (ASJ) AF: 0.00290 AC: 74 AN: 25512

East Asian (EAS) AF: 0.00 AC: 0 AN: 38746

South Asian (SAS) AF: 0.00 AC: 0 AN: 82624

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51318

Middle Eastern (MID) AF: 0.000349 AC: 2 AN: 5734

European-Non Finnish (NFE) AF: 0.0000227 AC: 25 AN: 1099644

Other (OTH) AF: 0.000202 AC: 12 AN: 59494

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152048 Hom.: 0 Cov.: 32 AF XY: 0.0000539 AC XY: 4 AN XY: 74274

African (AFR) AF: 0.0000242 AC: 1 AN: 41380

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000374 Hom.: 0

Bravo AF: 0.000113

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Congenital myasthenic syndrome 4C (3)
2	-	-	Congenital myasthenic syndrome 4A (2)
2	-	-	Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A (2)
2	-	-	not provided (2)
1	-	-	Congenital myasthenic syndrome (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.66
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs773526895; hg19: chr17-4802159;