rs757968612

Positions:

• chr17-4899375-C-G
• chr17-4899375-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000080.4(CHRNE):​c.1042G>C​(p.Glu348Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,096 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0710

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 4 ACMG points.

• PM1: In a topological_domain Cytoplasmic (size 127) in uniprot entity ACHE_HUMAN there are 8 pathogenic changes around while only 0 benign (100%) in NM_000080.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1042G>C	p.Glu348Gln	missense_variant	10/12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.1006G>C	p.Glu336Gln	missense_variant	11/13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1042G>C	p.Glu348Gln	missense_variant	10/12		NM_000080.4	ENSP00000497829	P1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 35

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152096 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74292

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.026	T
BayesDel_noAF	Benign	-0.27
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.28	.;T;D
M_CAP	Pathogenic	0.50	D
MetaRNN	Uncertain	0.52	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-1.0	N;.;.
REVEL	Uncertain	0.36
Sift	Benign	0.13	T;.;.
Sift4G	Benign	0.14	T;.;.
Polyphen		1.0	D;D;.
Vest4		0.23
MutPred		0.38		Gain of MoRF binding (P = 0.0265);Gain of MoRF binding (P = 0.0265);.;
MVP		0.87
MPC		0.68
ClinPred		0.90	D
GERP RS		3.7
Varity_R		0.38
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs757968612; hg19: chr17-4802670;