chr17-4901071-G-T

Position:

• chr17-4901071-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000080.4(CHRNE):​c.721C>A​(p.Leu241Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. L241F) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CHRNE NM_000080.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.14

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)

CHRNE (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr17-4901071-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.944

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.721C>A	p.Leu241Ile	missense_variant	7/12	ENST00000649488.2	NP_000071.1
C17orf107	NM_001145536.2	c.*538G>T		3_prime_UTR_variant	3/3	ENST00000381365.4	NP_001139008.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.721C>A	p.Leu241Ile	missense_variant	7/12		NM_000080.4	ENSP00000497829.1
C17orf107	ENST00000381365.4	c.*538G>T		3_prime_UTR_variant	3/3	2	NM_001145536.2	ENSP00000370770.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 250002 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135230

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461560 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 727088

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.47	T;T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Uncertain	2.8	M;M
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-1.8	N;.
REVEL	Pathogenic	0.77
Sift	Uncertain	0.0030	D;.
Sift4G	Uncertain	0.022	D;.
Polyphen		0.97	D;D
Vest4		0.68
MutPred		0.89		Gain of methylation at K239 (P = 0.0508);Gain of methylation at K239 (P = 0.0508);
MVP		0.90
MPC		0.72
ClinPred		0.97	D
GERP RS		3.9
Varity_R		0.72
gMVP		0.56

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

Publications

LitVar

Other links and lift over

dbSNP: rs28999110; hg19: chr17-4804366;