17-4901932-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000080.4(CHRNE):​c.500G>A​(p.Arg167His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,256 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R167L) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

CHRNE
NM_000080.4 missense, splice_region

Scores

3
13
3
Splicing: ADA: 1.000
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.71
Variant links:
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)

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_000080.4
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr17-4901932-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 18345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CHRNENM_000080.4 linkc.500G>A p.Arg167His missense_variant, splice_region_variant Exon 5 of 12 ENST00000649488.2 NP_000071.1 Q04844
C17orf107NM_001145536.2 linkc.*1399C>T 3_prime_UTR_variant Exon 3 of 3 ENST00000381365.4 NP_001139008.1 Q6ZR85

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CHRNEENST00000649488.2 linkc.500G>A p.Arg167His missense_variant, splice_region_variant Exon 5 of 12 NM_000080.4 ENSP00000497829.1 Q04844
C17orf107ENST00000381365.4 linkc.*1399C>T 3_prime_UTR_variant Exon 3 of 3 2 NM_001145536.2 ENSP00000370770.3 Q6ZR85

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461256
Hom.:
0
Cov.:
38
AF XY:
0.00000138
AC XY:
1
AN XY:
726922
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.070
CADD
Pathogenic
33
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.69
D;D
Eigen
Uncertain
0.63
Eigen_PC
Uncertain
0.56
FATHMM_MKL
Uncertain
0.80
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Pathogenic
0.41
D
MetaRNN
Pathogenic
0.86
D;D
MetaSVM
Uncertain
0.31
D
MutationAssessor
Uncertain
2.4
M;M
PrimateAI
Benign
0.40
T
PROVEAN
Uncertain
-2.5
N;.
REVEL
Uncertain
0.58
Sift
Uncertain
0.025
D;.
Sift4G
Uncertain
0.044
D;.
Polyphen
1.0
D;D
Vest4
0.57
MutPred
0.71
Gain of glycosylation at T170 (P = 0.0693);Gain of glycosylation at T170 (P = 0.0693);
MVP
0.91
MPC
0.77
ClinPred
0.99
D
GERP RS
4.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.40
gMVP
0.82

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
1.0
SpliceAI score (max)
0.72
Details are displayed if max score is > 0.2
DS_DL_spliceai
0.72
Position offset: 0

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-4805227; API