rs192195094

chr17-4899341-G-Achr17-4899341-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000080.4(CHRNE):c.1076C>T(p.Pro359Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000511 in 1,547,386 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P359S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0026 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.30

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008722782).
• BP6: Variant 17-4899341-G-A is Benign according to our data. Variant chr17-4899341-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 585672.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 = 0.00259 (394/152214) while in subpopulation AFR AF= 0.00878 (365/41554). AF 95% confidence interval is 0.00804. There are 3 homozygotes in gnomad4. There are 173 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.1076C>T	p.Pro359Leu	missense_variant	10/12	ENST00000649488.2
CHRNE	XM_017024115.2	c.1040C>T	p.Pro347Leu	missense_variant	11/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CHRNE	ENST00000649488.2	c.1076C>T	p.Pro359Leu	missense_variant	10/12		NM_000080.4	P1
CHRNE	ENST00000649830.1	c.143C>T	p.Pro48Leu	missense_variant	10/11
CHRNE	ENST00000572438.1	n.762C>T		non_coding_transcript_exon_variant	5/7	5
CHRNE	ENST00000652550.1	n.806C>T		non_coding_transcript_exon_variant	2/4

Frequencies

GnomAD3 genomes AF: 0.00260 AC: 395 AN: 152098 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00881

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000645 AC: 94 AN: 145708 Hom.: 1 AF XY: 0.000556 AC XY: 45 AN XY: 80934

Gnomad AFR exome AF: 0.00999

Gnomad AMR exome AF: 0.000461

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000127

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000856

Gnomad OTH exome AF: 0.000238

GnomAD4 exome AF: 0.000284 AC: 396 AN: 1395172 Hom.: 0 Cov.: 35 AF XY: 0.000258 AC XY: 178 AN XY: 690180

Gnomad4 AFR exome AF: 0.00887

Gnomad4 AMR exome AF: 0.000449

Gnomad4 ASJ exome AF: 0.0000400

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000993

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000452

Gnomad4 OTH exome AF: 0.000569

GnomAD4 genome AF: 0.00259 AC: 394 AN: 152214 Hom.: 3 Cov.: 32 AF XY: 0.00232 AC XY: 173 AN XY: 74422

Gnomad4 AFR AF: 0.00878

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000248 Hom.: 0

Bravo AF: 0.00294

ExAC AF: 0.000742 AC: 76

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital myasthenic syndrome 4A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

CHRNE-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 14, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

Nov 06, 2017

- -

Congenital myasthenic syndrome Benign:1

Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;D;.
Eigen	Uncertain	0.23
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.68	D
MetaRNN	Benign	0.0087	T;T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	1.1	L;L;.
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-2.0	N;.;.
REVEL	Uncertain	0.38
Sift	Benign	0.15	T;.;.
Sift4G	Benign	0.25	T;.;.
Polyphen		0.97	D;D;.
Vest4		0.24
MVP		0.93
MPC		0.17
ClinPred		0.050	T
GERP RS		4.9
Varity_R		0.099
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs192195094; hg19: chr17-4802636;