17-4899511-T-G

Variant names:

• chr17-4899511-T-G
• rs747017964
• NM_000080.4:c.989A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000080.4(CHRNE):​c.989A>C​(p.Gln330Pro) 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. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q330R) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.84
• Publications: 1 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 17 uncertain in NM_000080.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34903157).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.989A>C	p.Gln330Pro	missense_variant	Exon 9 of 12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.-252T>G		upstream_gene_variant		ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.989A>C	p.Gln330Pro	missense_variant	Exon 9 of 12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.-252T>G		upstream_gene_variant		2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.55
BayesDel_addAF	Benign	-0.055	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	21
DANN	Benign	0.86
DEOGEN2	Benign	0.38	T;T;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.45	N
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.17	D
MetaRNN	Benign	0.35	T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	0.0	N;N;.
PhyloP100		2.8
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.2	N;.;.
REVEL	Benign	0.22
Sift	Uncertain	0.028	D;.;.
Sift4G	Benign	0.10	T;.;.
Polyphen		0.0050	B;B;.
Vest4		0.27
MutPred		0.69		Gain of glycosylation at Q330 (P = 0.0127);Gain of glycosylation at Q330 (P = 0.0127);.;
MVP		0.81
MPC		0.21
ClinPred		0.50	T
GERP RS		3.6
PromoterAI		-0.035	Neutral
Varity_R		0.44
gMVP		0.79

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

Other links and lift over

dbSNP: rs747017964; hg19: chr17-4802806;