chr17-4898114-G-A

Variant names:

• chr17-4898114-G-A
• rs886053117
• NM_000080.4:c.*622C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_000080.4(CHRNE):​c.*622C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000313 in 159,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: CHRNE NM_000080.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.166
• 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]

MINK1 (HGNC:17565): (misshapen like kinase 1) This gene encodes a serine/threonine kinase belonging to the germinal center kinase (GCK) family. The protein is structurally similar to the kinases that are related to NIK and may belong to a distinct subfamily of NIK-related kinases within the GCK family. Studies of the mouse homolog indicate an up-regulation of expression in the course of postnatal mouse cerebral development and activation of the cJun N-terminal kinase (JNK) and the p38 pathways. [provided by RefSeq, Mar 2016]

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CHRNE	NM_000080.4	c.*622C>T		3_prime_UTR_variant	Exon 12 of 12	ENST00000649488.2	NP_000071.1
MINK1	NM_153827.5	c.*827G>A		downstream_gene_variant		ENST00000355280.11	NP_722549.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CHRNE	ENST00000649488.2	c.*622C>T		3_prime_UTR_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1
MINK1	ENST00000355280.11	c.*827G>A		downstream_gene_variant		1	NM_153827.5	ENSP00000347427.6

Frequencies

GnomAD3 genomes AF: 0.0000201 AC: 3 AN: 149588 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000660

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000199 AC: 2 AN: 10074 Hom.: 0 Cov.: 0 AF XY: 0.000189 AC XY: 1 AN XY: 5292

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 76

American (AMR) AF: 0.00 AC: 0 AN: 2192

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 62

East Asian (EAS) AF: 0.00 AC: 0 AN: 434

South Asian (SAS) AF: 0.00132 AC: 2 AN: 1516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 136

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 22

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 5250

Other (OTH) AF: 0.00 AC: 0 AN: 386

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.002339), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000200 AC: 3 AN: 149724 Hom.: 0 Cov.: 31 AF XY: 0.0000273 AC XY: 2 AN XY: 73148

African (AFR) AF: 0.00 AC: 0 AN: 41198

American (AMR) AF: 0.00 AC: 0 AN: 15104

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 4890

South Asian (SAS) AF: 0.000659 AC: 3 AN: 4550

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67340

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	3.3
DANN	Benign	0.71
PhyloP100		0.17

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: rs886053117; hg19: chr17-4801409;