17-4899036-C-T

Position:

• chr17-4899036-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM5 PP3

The NM_000080.4(CHRNE):​c.1291G>A​(p.Ala431Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,458,552 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. A431P) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.21

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]

CHRNE (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 5 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-4899036-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.799

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.1291G>A	p.Ala431Thr	missense_variant	11/12	ENST00000649488.2	NP_000071.1
CHRNE	XM_017024115.2	c.1255G>A	p.Ala419Thr	missense_variant	12/13		XP_016879604.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.1291G>A	p.Ala431Thr	missense_variant	11/12		NM_000080.4	ENSP00000497829.1
CHRNE	ENST00000649830.1	c.358G>A	p.Ala120Thr	missense_variant	11/11			ENSP00000496907.1
CHRNE	ENST00000572438.1	n.977G>A		non_coding_transcript_exon_variant	6/7	5
CHRNE	ENST00000652550.1	n.1021G>A		non_coding_transcript_exon_variant	3/4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1458552 Hom.: 0 Cov.: 36 AF XY: 0.00000138 AC XY: 1 AN XY: 725346

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: 0.0000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000312 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.099
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.42	T;T;.
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.77	.;T;T
M_CAP	Uncertain	0.092	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Uncertain	2.6	M;M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-2.2	N;.;.
REVEL	Uncertain	0.56
Sift	Benign	0.072	T;.;.
Sift4G	Benign	0.11	T;.;.
Polyphen		0.97	D;D;.
Vest4		0.37
MVP		0.92
MPC		0.17
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.27
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909517; hg19: chr17-4802331;