rs756786529

Variant names:

• chr17-4899275-G-A
• rs756786529
• NM_000080.4:c.1142C>T

Your query was ambiguous. Multiple possible variants found:

• chr17-4899275-G-A
• chr17-4899275-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_000080.4(CHRNE):​c.1142C>T​(p.Ala381Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000181 in 1,601,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A381T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 7.64
• 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 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.832

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000080.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	NM_000080.4	MANE Select	c.1142C>T	p.Ala381Val	missense	Exon 10 of 12	NP_000071.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1142C>T	p.Ala381Val	missense	Exon 10 of 12	ENSP00000497829.1
	CHRNE	ENST00000649830.1		c.209C>T	p.Ala70Val	missense	Exon 10 of 11	ENSP00000496907.1
	CHRNE	ENST00000572438.1	TSL:5	n.828C>T		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151872 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000219 AC: 5 AN: 228216 AF XY: 0.0000159

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000207

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000292

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000179 AC: 26 AN: 1449776 Hom.: 0 Cov.: 35 AF XY: 0.0000111 AC XY: 8 AN XY: 721478

African (AFR) AF: 0.0000600 AC: 2 AN: 33320

American (AMR) AF: 0.0000225 AC: 1 AN: 44530

Ashkenazi Jewish (ASJ) AF: 0.000153 AC: 4 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.00 AC: 0 AN: 85814

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44180

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5696

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1110546

Other (OTH) AF: 0.0000166 AC: 1 AN: 60148

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151872 Hom.: 0 Cov.: 32 AF XY: 0.0000270 AC XY: 2 AN XY: 74172

African (AFR) AF: 0.0000242 AC: 1 AN: 41332

American (AMR) AF: 0.00 AC: 0 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 67928

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.0000262 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.00000830 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myasthenic syndrome (1)
-	1	-	Congenital myasthenic syndrome 4A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.62	D
Eigen	Pathogenic	0.78
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	D
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.45	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		7.6
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0090	D
Polyphen		1.0	D
Vest4		0.58
MVP		0.94
MPC		0.65
ClinPred		0.97	D
GERP RS		4.7
PromoterAI		-0.046	Neutral
Varity_R		0.32
gMVP		0.58
Mutation Taster		=66/34	polymorphism

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: rs756786529; hg19: chr17-4802570;