rs72835059

Positions:

• chr17-4902094-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000080.4(CHRNE):​c.345-7C>T 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 0.0835 in 1,613,774 control chromosomes in the GnomAD database, including 6,107 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (448 hom., cov: 32)
  • Exomes 𝑓: 0.085 (5659 hom.)
• Consequence: CHRNE NM_000080.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.02643
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.559

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-4902094-G-A is Benign according to our data. Variant chr17-4902094-G-A is described in ClinVar as [Benign]. Clinvar id is 128765.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-4902094-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0917 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
C17orf107	NM_001145536.2	c.*1561G>A		3_prime_UTR_variant	3/3	ENST00000381365.4	NP_001139008.1
CHRNE	NM_000080.4	c.345-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000649488.2	NP_000071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
C17orf107	ENST00000381365.4	c.*1561G>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770	A2
CHRNE	ENST00000649488.2	c.345-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_000080.4	ENSP00000497829	P1
CHRNE	ENST00000649830.1	c.-589-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant				ENSP00000496907
CHRNE	ENST00000575637.1	n.166-7C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0724 AC: 10994 AN: 151950 Hom.: 447 Cov.: 32

Gnomad AFR AF: 0.0312

Gnomad AMI AF: 0.116

Gnomad AMR AF: 0.0601

Gnomad ASJ AF: 0.0648

Gnomad EAS AF: 0.0494

Gnomad SAS AF: 0.0336

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0936

Gnomad OTH AF: 0.0584

GnomAD3 exomes AF: 0.0741 AC: 18597 AN: 250942 Hom.: 856 AF XY: 0.0743 AC XY: 10085 AN XY: 135756

Gnomad AFR exome AF: 0.0280

Gnomad AMR exome AF: 0.0471

Gnomad ASJ exome AF: 0.0602

Gnomad EAS exome AF: 0.0426

Gnomad SAS exome AF: 0.0287

Gnomad FIN exome AF: 0.138

Gnomad NFE exome AF: 0.0949

Gnomad OTH exome AF: 0.0821

GnomAD4 exome AF: 0.0846 AC: 123724 AN: 1461702 Hom.: 5659 Cov.: 37 AF XY: 0.0833 AC XY: 60570 AN XY: 727138

Gnomad4 AFR exome AF: 0.0279

Gnomad4 AMR exome AF: 0.0477

Gnomad4 ASJ exome AF: 0.0592

Gnomad4 EAS exome AF: 0.0698

Gnomad4 SAS exome AF: 0.0292

Gnomad4 FIN exome AF: 0.135

Gnomad4 NFE exome AF: 0.0915

Gnomad4 OTH exome AF: 0.0747

GnomAD4 genome AF: 0.0723 AC: 10993 AN: 152072 Hom.: 448 Cov.: 32 AF XY: 0.0739 AC XY: 5494 AN XY: 74350

Gnomad4 AFR AF: 0.0312

Gnomad4 AMR AF: 0.0601

Gnomad4 ASJ AF: 0.0648

Gnomad4 EAS AF: 0.0495

Gnomad4 SAS AF: 0.0336

Gnomad4 FIN AF: 0.144

Gnomad4 NFE AF: 0.0936

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0811 Hom.: 233

Bravo AF: 0.0620

Asia WGS AF: 0.0390 AC: 136 AN: 3478

EpiCase AF: 0.0893

EpiControl AF: 0.0897

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 29, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Congenital myasthenic syndrome Benign:2

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Congenital myasthenic syndrome 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	8.2
DANN	Benign	0.93

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.026
dbscSNV1_RF	Benign	0.022
SpliceAI score (max)		0.080		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

Other links and lift over

dbSNP: rs72835059; hg19: chr17-4805389; COSMIC: COSV53420793; COSMIC: COSV53420793;