17-4899112-C-T

Position:

chr17-4899112-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000080.4(CHRNE):c.1220-5G>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000553 in 1,606,098 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0026 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00034 ( 2 hom. )

Consequence

CHRNE
NM_000080.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0001060

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -1.53

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BP6

Variant 17-4899112-C-T is Benign according to our data. Variant chr17-4899112-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 323982.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00262 (397/151502) while in subpopulation AFR AF= 0.00893 (369/41324). AF 95% confidence interval is 0.00818. There are 1 homozygotes in gnomad4. There are 184 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4 linkuse as main transcript	c.1220-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000649488.2
CHRNE	XM_017024115.2 linkuse as main transcript	c.1184-5G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
CHRNE	ENST00000649488.2 linkuse as main transcript	c.1220-5G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		NM_000080.4	P1
CHRNE	ENST00000649830.1 linkuse as main transcript	c.287-5G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
CHRNE	ENST00000572438.1 linkuse as main transcript	n.906-5G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant	5
CHRNE	ENST00000652550.1 linkuse as main transcript	n.950-5G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00261

AC:

395

AN:

151384

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00893

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000591

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000209

Gnomad FIN

AF:

0.0000950

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000221

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.000638

AC:

146

AN:

228696

Hom.:

AF XY:

0.000485

AC XY:

AN XY:

125822

show subpopulations

Gnomad AFR exome

AF:

0.00906

Gnomad AMR exome

AF:

0.000300

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000541

Gnomad NFE exome

AF:

0.000148

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000338

AC:

491

AN:

1454596

Hom.:

Cov.:

AF XY:

0.000295

AC XY:

213

AN XY:

723252

show subpopulations

Gnomad4 AFR exome

AF:

0.00864

Gnomad4 AMR exome

AF:

0.000430

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000117

Gnomad4 FIN exome

AF:

0.0000398

Gnomad4 NFE exome

AF:

0.000144

Gnomad4 OTH exome

AF:

0.000333

GnomAD4 genome

AF:

0.00262

AC:

397

AN:

151502

Hom.:

Cov.:

AF XY:

0.00248

AC XY:

184

AN XY:

74078

show subpopulations

Gnomad4 AFR

AF:

0.00893

Gnomad4 AMR

AF:

0.000591

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000419

Gnomad4 FIN

AF:

0.0000950

Gnomad4 NFE

AF:

0.000221

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.00101

Hom.:

Bravo

AF:

0.00306

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2022	CHRNE: BP4, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 15, 2021	- -

Congenital myasthenic syndrome

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, no assertion criteria provided	clinical testing	Natera, Inc.	Oct 25, 2019	- -

Congenital myasthenic syndrome 4A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

4.3

DANN

Benign

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00011

dbscSNV1_RF

Benign

0.016

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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