17-4899375-C-T

Variant names:

• chr17-4899375-C-T
• rs757968612
• NM_000080.4:c.1042G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM1

The NM_000080.4(CHRNE):​c.1042G>A​(p.Glu348Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000221 in 1,533,336 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00023 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• Conservation: PhyloP100: 0.0710
• Publications: 0 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 2 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 28 uncertain in NM_000080.4

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.1042G>A	p.Glu348Lys	missense	Exon 10 of 12	NP_000071.1
	C17orf107	NM_001145536.2	MANE Select	c.-388C>T		upstream_gene	N/A	NP_001139008.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CHRNE	ENST00000649488.2	MANE Select	c.1042G>A	p.Glu348Lys	missense	Exon 10 of 12	ENSP00000497829.1
	CHRNE	ENST00000649830.1		c.109G>A	p.Glu37Lys	missense	Exon 10 of 11	ENSP00000496907.1
	CHRNE	ENST00000572438.1	TSL:5	n.728G>A		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152096 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000760 AC: 10 AN: 131584 AF XY: 0.0000690

Gnomad AFR exome AF: 0.000150

Gnomad AMR exome AF: 0.0000443

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000161

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000232 AC: 321 AN: 1381240 Hom.: 0 Cov.: 35 AF XY: 0.000219 AC XY: 149 AN XY: 681762

African (AFR) AF: 0.0000640 AC: 2 AN: 31234

American (AMR) AF: 0.0000297 AC: 1 AN: 33636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24318

East Asian (EAS) AF: 0.00 AC: 0 AN: 35884

South Asian (SAS) AF: 0.00 AC: 0 AN: 78788

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4730

European-Non Finnish (NFE) AF: 0.000288 AC: 310 AN: 1076758

Other (OTH) AF: 0.000139 AC: 8 AN: 57406

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152096 Hom.: 0 Cov.: 33 AF XY: 0.000135 AC XY: 10 AN XY: 74292

African (AFR) AF: 0.0000724 AC: 3 AN: 41446

American (AMR) AF: 0.000393 AC: 6 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67994

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

Alfa AF: 0.0000397 Hom.: 0

Bravo AF: 0.000132

ExAC AF: 0.0000320 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	CHRNE-related disorder (1)
-	1	-	Congenital myasthenic syndrome (1)
-	1	-	Congenital myasthenic syndrome 4A (1)
-	1	-	Congenital myasthenic syndrome 4C;C4225369:Congenital myasthenic syndrome 4B;C4225413:Congenital myasthenic syndrome 4A (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.090
Eigen_PC	Benign	-0.057
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.52	T
M_CAP	Pathogenic	0.74	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.13	T
MutationAssessor	Benign	0.81	L
PhyloP100		0.071
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.42
Sift	Benign	0.19	T
Sift4G	Benign	0.22	T
Polyphen		0.46	P
Vest4		0.47
MVP		0.90
MPC		0.71
ClinPred		0.13	T
GERP RS		3.7
PromoterAI		-0.017	Neutral
Varity_R		0.41
gMVP		0.57
Mutation Taster		=71/29	polymorphism

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

Other links and lift over

dbSNP: rs757968612; hg19: chr17-4802670; COSMIC: COSV104541148; COSMIC: COSV104541148;