ENST00000574453.5:n.*4259C>G

Variant names:

• chr17-4897878-C-G
• rs375660349
• ENST00000574453.5:n.*4259C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The ENST00000574453.5(MINK1):​n.*4259C>G variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 149,322 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MINK1 ENST00000574453.5 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.145
• Publications: 0 publications found

Genes affected

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]

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 Gene-Disease associations (from GenCC):

• congenital myasthenic syndrome

  Inheritance: AR Classification: DEFINITIVE Submitted by: Illumina
• congenital myasthenic syndrome 4A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4B

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), PanelApp Australia
• congenital myasthenic syndrome 4C

  Inheritance: AR Classification: STRONG Submitted by: Genomics England PanelApp
• postsynaptic congenital myasthenic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-4897878-C-G is Benign according to our data. Variant chr17-4897878-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 323949.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 194 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MINK1	NM_153827.5	c.*591C>G		3_prime_UTR_variant	Exon 32 of 32	ENST00000355280.11	NP_722549.2
CHRNE	NM_000080.4	c.*858G>C		3_prime_UTR_variant	Exon 12 of 12	ENST00000649488.2	NP_000071.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MINK1	ENST00000355280.11	c.*591C>G		3_prime_UTR_variant	Exon 32 of 32	1	NM_153827.5	ENSP00000347427.6
CHRNE	ENST00000649488.2	c.*858G>C		3_prime_UTR_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1

Frequencies

GnomAD3 genomes AF: 0.00129 AC: 193 AN: 149202 Hom.: 2 Cov.: 29

Gnomad AFR AF: 0.0000732

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000600

Gnomad ASJ AF: 0.0196

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0138

Gnomad FIN AF: 0.000302

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000629

Gnomad OTH AF: 0.00146

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 674 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 374

African (AFR) AF: 0.00 AC: 0 AN: 6

American (AMR) AF: 0.00 AC: 0 AN: 6

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.00 AC: 0 AN: 34

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 234

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 366

Other (OTH) AF: 0.00 AC: 0 AN: 24

GnomAD4 genome AF: 0.00130 AC: 194 AN: 149322 Hom.: 2 Cov.: 29 AF XY: 0.00139 AC XY: 101 AN XY: 72828

African (AFR) AF: 0.0000730 AC: 3 AN: 41080

American (AMR) AF: 0.000599 AC: 9 AN: 15020

Ashkenazi Jewish (ASJ) AF: 0.0196 AC: 67 AN: 3426

East Asian (EAS) AF: 0.00 AC: 0 AN: 5092

South Asian (SAS) AF: 0.0141 AC: 66 AN: 4694

European-Finnish (FIN) AF: 0.000302 AC: 3 AN: 9948

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000629 AC: 42 AN: 66804

Other (OTH) AF: 0.00145 AC: 3 AN: 2070

Alfa AF: 0.00122 Hom.: 0

Bravo AF: 0.000986

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	1.7
DANN	Benign	0.50
PhyloP100		0.14
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs375660349; hg19: chr17-4801173;