rs762704832

Variant names:

• chr17-4900909-TGGAG-T
• rs762704832
• NM_001145536.2:c.*381_*384delGGAG

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PP3_Moderate

The NM_000080.4(CHRNE):​c.803-6_803-3delCTCC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000958 in 1,461,788 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: CHRNE NM_000080.4 splice_region, intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 B:1
• Conservation: PhyloP100: 2.95
• Publications: 0 publications found

Genes affected

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

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: Uncertain_significance. The variant received 2 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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
	C17orf107	NM_001145536.2	MANE Select	c.*381_*384delGGAG		3_prime_UTR	Exon 3 of 3	NP_001139008.1	Q6ZR85
	CHRNE	NM_000080.4	MANE Select	c.803-6_803-3delCTCC		splice_region intron	N/A	NP_000071.1	Q04844

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	C17orf107	ENST00000381365.4	TSL:2 MANE Select	c.*381_*384delGGAG		3_prime_UTR	Exon 3 of 3	ENSP00000370770.3	Q6ZR85
	CHRNE	ENST00000649488.2	MANE Select	c.803-6_803-3delCTCC		splice_region intron	N/A	ENSP00000497829.1	Q04844
	C17orf107	ENST00000861085.1		c.*381_*384delGGAG		3_prime_UTR	Exon 3 of 3	ENSP00000531144.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000120 AC: 3 AN: 250186 AF XY: 0.0000148

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461788 Hom.: 0 AF XY: 0.0000110 AC XY: 8 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.0000447 AC: 2 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000989 AC: 11 AN: 1111960

Other (OTH) AF: 0.00 AC: 0 AN: 60382

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000660 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=32/68	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.88		Position offset: -2

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

Other links and lift over

dbSNP: rs762704832; hg19: chr17-4804204;