Variant rs990457690 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP5BP4

The ENST00000649830.1(CHRNE):c.-887-395G>A variant causes a intron change. The variant allele was found at a frequency of 0.00000459 in 1,306,672 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000026 ( 0 hom. )

Consequence

CHRNE
ENST00000649830.1 intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 4.00

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:):

C17orf107 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PP5

Variant 17-4903158-C-T is Pathogenic according to our data. Variant chr17-4903158-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 465866.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Pathogenic=1, Likely_pathogenic=3}. Variant chr17-4903158-C-T is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.28). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Protein
CHRNE	XM_017024115.2 linkuse as main transcript	c.11-395G>A	intron_variant	XP_016879604.1
C17orf107	XR_007065253.1 linkuse as main transcript	n.2388+1037C>T	intron_variant
C17orf107	XR_007065254.1 linkuse as main transcript	n.2388+1037C>T	intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649830.1 linkuse as main transcript	c.-887-395G>A		intron_variant				ENSP00000496907.1		A0A3B3IRM1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

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

GnomAD4 exome

AF:

0.00000260

AC:

AN:

1154590

Hom.:

AF XY:

0.00000171

AC XY:

AN XY:

584924

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000354

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152082

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.0000725

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 4A

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 29, 2023	This variant has been observed in individuals with autosomal recessive congenital myasthenic syndrome (PMID: 10382905). It has also been observed to segregate with disease in related individuals. This variant is also known as -155G>A. ClinVar contains an entry for this variant (Variation ID: 465866). Algorithms developed to predict the effect of variants on protein structure and function are not available or were not evaluated for this variant. This variant affects a highly conserved nucleotide within the N-box motif of the CHRNE promoter region of CHRNE termed the N-box. Experimental studies show that variants affecting the N-box motif impair DNA-binding efficiency and epsilon subunit transcription, which drives synapse-specific CHRNE expression (PMID: 8663316, 9606190). Adjacent variants within the N-box (c.-94G>A, c.-96C>T) have also been observed to segregate with congenital myasthenic syndrome in affected families (PMID: 10211467, 11960891) and functional studies show that they affect CHRNE expression (PMID: 8663316, 9606190). This suggests that the N-box is important for CHRNE expression, and that other variants in this motif may also be pathogenic. This variant is present in population databases (no rsID available, gnomAD 0.02%). For these reasons, this variant has been classified as Pathogenic. This variant occurs in a non-coding region of the CHRNE gene. It does not change the encoded amino acid sequence of the CHRNE protein. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Feb 22, 2024	- -

not provided

Pathogenic:1Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2023	Previously reported in an individual with congenital myasthenia syndrome who had a second CHRNE variant; however segregation information was not reported (PMID: 33756069); Published functional studies suggest that the variant is located in a promoter region of CHRNE and results in reduced gene expression (PMID: 8663316); Also known as c.-155G>A; This variant is associated with the following publications: (PMID: 8663316, 33756069, 10382905) -
Likely pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2021	- -

Congenital myasthenic syndrome 4B

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Dec 12, 2019

This variant was determined to be likely pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Benign

0.86

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