rs747853975

Variant names:

• chr17-4899206-G-A
• rs747853975
• NM_000080.4:c.1211C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The ENST00000649488.2(CHRNE):​c.1211C>T​(p.Thr404Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000038 in 1,604,692 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T404T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000040 (0 hom.)
• Consequence: CHRNE ENST00000649488.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 0.193
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22619289).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000649488.2. 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.1211C>T	p.Thr404Ile	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.1211C>T	p.Thr404Ile	missense	Exon 10 of 12	ENSP00000497829.1
	CHRNE	ENST00000649830.1		c.278C>T	p.Thr93Ile	missense	Exon 10 of 11	ENSP00000496907.1
	CHRNE	ENST00000572438.1	TSL:5	n.897C>T		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

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: 0.000478

GnomAD2 exomes AF: 0.0000261 AC: 6 AN: 229716 AF XY: 0.0000237

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000592

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000392

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000399 AC: 58 AN: 1452522 Hom.: 0 Cov.: 35 AF XY: 0.0000415 AC XY: 30 AN XY: 722474

African (AFR) AF: 0.0000300 AC: 1 AN: 33296

American (AMR) AF: 0.0000450 AC: 2 AN: 44412

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26024

East Asian (EAS) AF: 0.00 AC: 0 AN: 39270

South Asian (SAS) AF: 0.00 AC: 0 AN: 85442

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 0.0000450 AC: 50 AN: 1109922

Other (OTH) AF: 0.0000832 AC: 5 AN: 60078

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152170 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74330

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68012

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Congenital myasthenic syndrome (1)
-	1	-	Congenital myasthenic syndrome 4A (1)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	17
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.30	T
M_CAP	Uncertain	0.27	D
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	0.28	N
PhyloP100		0.19
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	0.82	N
REVEL	Uncertain	0.29
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
Polyphen		0.17	B
Vest4		0.22
MutPred		0.59		Loss of disorder (P = 0.077)
MVP		0.89
MPC		0.22
ClinPred		0.093	T
GERP RS		4.9
PromoterAI		0.029	Neutral
Varity_R		0.070
gMVP		0.25
Mutation Taster		=84/16	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: rs747853975; hg19: chr17-4802501;