rs768552387

Positions:

chr17-4901621-G-GAGAGCTGCGGAGCC

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1PP5

The NM_000080.4(CHRNE):c.504_505insGGCTCCGCAGCTCT(p.Gln169GlyfsTer19) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000136 in 1,613,826 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000096 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 frameshift

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: -0.473

Variant links:

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 links:

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

C17orf107 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 17-4901621-G-GAGAGCTGCGGAGCC is Pathogenic according to our data. Variant chr17-4901621-G-GAGAGCTGCGGAGCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465862.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4 linkuse as main transcript	c.504_505insGGCTCCGCAGCTCT	p.Gln169GlyfsTer19	frameshift_variant	6/12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2 linkuse as main transcript	c.1091_1104dup		3_prime_UTR_variant	3/3	ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2 linkuse as main transcript	c.504_505insGGCTCCGCAGCTCT	p.Gln169GlyfsTer19	frameshift_variant	6/12		NM_000080.4	ENSP00000497829	P1
C17orf107	ENST00000381365.4 linkuse as main transcript	c.1091_1104dup		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770	A2

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152208

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000280

AC:

AN:

249974

Hom.:

AF XY:

0.0000370

AC XY:

AN XY:

135286

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000958

AC:

AN:

1461618

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000104

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152208

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.000169

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000110

Hom.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 4A

Pathogenic:2Uncertain:1

Likely pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Sep 22, 2023	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. ClinVar contains an entry for this variant (Variation ID: 465862). This variant is also known as p.Gln169Glyfs*19. This sequence change falls in intron 5 of the CHRNE gene. It does not directly change the encoded amino acid sequence of the CHRNE protein. This variant is present in population databases (rs768552387, gnomAD 0.01%). This variant has been observed in individuals with clinical features of autosomal recessive congenital myasthenic syndrome (Invitae). -
Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jan 20, 2024	- -
Pathogenic, no assertion criteria provided	research	MOLECULAR BIOLOGY AND HUMAN GENETICS DIVISION, THE UNIVERSITY OF BURDWAN	Jun 21, 2021	A 16-year-old boy presented with progressive upward gaze palsy with repetitive falls & trauma along with progressive weakness at proximal muscles of the lower limb which was worsened after the exercise and repeated use. Limb weakness increases at the end of the day. Also, he presented with ptosis in both eyes followed by Anti ACTHR Ab and Anti MUSK Ab were negative and elevated serum lactate. We considered this variant (NM_000080: exon6: c.504_505ins GGCTCCGCAGCTCT: p.Q169Gfs*19) as pathogenic because Splice AI prediction showed the significant change like Acceptor Gain score 0.80. Also, CADD score 32.0 represented as disease causing. This variant was presented as homozygous condition and it produces truncated protein after the p.Q169G substitution, premature termination of translation occurs after 19 amino acids downstream. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 15, 2020

- -

Congenital myasthenic syndrome

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 27, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over