17-4901554-T-A

Position:

• chr17-4901554-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000080.4(CHRNE):​c.572A>T​(p.Lys191Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.75

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]

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

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a topological_domain Extracellular (size 218) in uniprot entity ACHE_HUMAN there are 22 pathogenic changes around while only 0 benign (100%) in NM_000080.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34096843).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.572A>T	p.Lys191Met	missense_variant	6/12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*1021T>A		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	c.572A>T	p.Lys191Met	missense_variant	6/12		NM_000080.4	ENSP00000497829	P1
C17orf107	ENST00000381365.4	c.*1021T>A		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome 4A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 10, 2017

This sequence change replaces lysine with methionine at codon 191 of the CHRNE protein (p.Lys191Met). The lysine residue is weakly conserved and there is a moderate physicochemical difference between lysine and methionine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CHRNE-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T;T
Eigen	Benign	0.19
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.73	.;T
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.1	M;M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.41	N;.
REVEL	Uncertain	0.37
Sift	Benign	0.038	D;.
Sift4G	Uncertain	0.030	D;.
Polyphen		0.81	P;P
Vest4		0.44
MutPred		0.43		Loss of ubiquitination at K191 (P = 0.0141);Loss of ubiquitination at K191 (P = 0.0141);
MVP		0.88
MPC		0.66
ClinPred		0.79	D
GERP RS		4.6
Varity_R		0.15
gMVP		0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1555546863; hg19: chr17-4804849;