17-4899384-C-CCTGGGG

Variant names:

• chr17-4899384-C-CCTGGGG
• rs886053123
• NM_000080.4:c.1033-6_1033-1dupCCCCAG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000080.4(CHRNE):​c.1033-6_1033-1dupCCCCAG variant causes a splice acceptor, intron change. The variant allele was found at a frequency of 0.00000362 in 1,381,554 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CHRNE NM_000080.4 splice_acceptor, intron
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 3.71
• 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.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage

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.1033-6_1033-1dupCCCCAG		splice_acceptor intron	N/A	NP_000071.1	Q04844
	C17orf107	NM_001145536.2	MANE Select	c.-379_-378insCTGGGG		upstream_gene	N/A	NP_001139008.1	Q6ZR85

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1033-1_1033insCCCCAG		splice_acceptor intron	N/A	ENSP00000497829.1	Q04844
	CHRNE	ENST00000649830.1		c.100-1_100insCCCCAG		splice_acceptor intron	N/A	ENSP00000496907.1	A0A3B3IRM1
	CHRNE	ENST00000572438.1	TSL:5	n.719-1_719insCCCCAG		splice_acceptor intron	N/A

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000756 AC: 1 AN: 132272 AF XY: 0.0000138

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000362 AC: 5 AN: 1381554 Hom.: 0 Cov.: 35 AF XY: 0.00000733 AC XY: 5 AN XY: 681772

African (AFR) AF: 0.00 AC: 0 AN: 31210

American (AMR) AF: 0.00 AC: 0 AN: 33726

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24364

East Asian (EAS) AF: 0.00 AC: 0 AN: 35878

South Asian (SAS) AF: 0.0000635 AC: 5 AN: 78798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39226

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4714

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076276

Other (OTH) AF: 0.00 AC: 0 AN: 57362

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome 4A (1)
-	1	-	Congenital Myasthenic Syndrome, Dominant/Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7

Splicing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs886053123; hg19: chr17-4802679;