NM_000080.4:c.1327delG

Variant names:

• chr17-4898890-TC-T
• rs763258280
• NM_000080.4:c.1327delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1_Strong PS3 PP3_Moderate PP5_Very_Strong

The NM_000080.4(CHRNE):​c.1327delG​(p.Glu443LysfsTer64) variant causes a frameshift, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000596 in 1,577,704 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000641247: Experimental studies have shown that this frameshift affects CHRNE function (PMID:10514102)." and additional evidence is available in ClinVar. Synonymous variant affecting the same amino acid position (i.e. E443E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000065 (0 hom.)
• Consequence: CHRNE NM_000080.4 frameshift, splice_region
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:27 O:1
• Conservation: PhyloP100: 7.64
• Publications: 14 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: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 18 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 15 pathogenic variants in the truncated region.
• PS3: PS3 evidence extracted from ClinVar submissions: SCV000641247: Experimental studies have shown that this frameshift affects CHRNE function (PMID: 10514102).; SCV004048044: Experimental studies have shown that this frameshift affects CHRNE function (Yang Y et.al.,2014).; SCV004176607: Experimental studies have shown that this frameshift affects CHRNE function (Croxen R et al. 1999).
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 17-4898890-TC-T is Pathogenic according to our data. Variant chr17-4898890-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 243031.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.1327delG	p.Glu443LysfsTer64	frameshift splice_region	Exon 12 of 12	NP_000071.1	Q04844

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1327delG	p.Glu443LysfsTer64	frameshift splice_region	Exon 12 of 12	ENSP00000497829.1	Q04844
	CHRNE	ENST00000649830.1		c.503delG	p.Gly168GlufsTer52	frameshift	Exon 11 of 11	ENSP00000496907.1	A0A3B3IRM1
	CHRNE	ENST00000572438.1	TSL:5	n.1013delG		splice_region non_coding_transcript_exon	Exon 7 of 7

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000128 AC: 24 AN: 188070 AF XY: 0.000179

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000250

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000652 AC: 93 AN: 1425664 Hom.: 0 Cov.: 34 AF XY: 0.0000921 AC XY: 65 AN XY: 705750

African (AFR) AF: 0.00 AC: 0 AN: 32922

American (AMR) AF: 0.00 AC: 0 AN: 37856

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25378

East Asian (EAS) AF: 0.00 AC: 0 AN: 38262

South Asian (SAS) AF: 0.000783 AC: 64 AN: 81764

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5720

European-Non Finnish (NFE) AF: 0.0000219 AC: 24 AN: 1094252

Other (OTH) AF: 0.0000845 AC: 5 AN: 59138

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152040 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74256

African (AFR) AF: 0.0000241 AC: 1 AN: 41410

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

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: 0.00 AC: 0 AN: 67982

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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000453

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
7	-	-	Congenital myasthenic syndrome 4A (7)
7	-	-	Congenital myasthenic syndrome 4C (7)
6	-	-	not provided (6)
3	-	-	Congenital myasthenic syndrome 4B (3)
2	-	-	Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A (2)
1	-	-	Congenital myasthenic syndrome (2)
1	-	-	Congenital myasthenic syndrome 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		7.6
Mutation Taster		=4/196	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.90		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.44		Position offset: 0
DS_AL_spliceai		0.90		Position offset: 1

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

Other links and lift over

dbSNP: rs763258280; hg19: chr17-4802185; COSMIC: COSV104395703; COSMIC: COSV104395703;