ENST00000574453.5:n.*4372C>T

Variant names:

• chr17-4897991-C-T
• rs1053751
• ENST00000574453.5:n.*4372C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000574453.5(MINK1):​n.*4372C>T 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 0.818 in 145,204 control chromosomes in the GnomAD database, including 48,638 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.82 (48638 hom., cov: 23)
  • Exomes 𝑓: 0.76 (114 hom.)
  • Failed GnomAD Quality Control
• Consequence: MINK1 ENST00000574453.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.238
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 17-4897991-C-T is Benign according to our data. Variant chr17-4897991-C-T is described in ClinVar as [Benign]. Clinvar id is 323958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.858 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MINK1	NM_153827.5	c.*704C>T		3_prime_UTR_variant	Exon 32 of 32	ENST00000355280.11	NP_722549.2
CHRNE	NM_000080.4	c.*745G>A		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.*704C>T		3_prime_UTR_variant	Exon 32 of 32	1	NM_153827.5	ENSP00000347427.6
CHRNE	ENST00000649488.2	c.*745G>A		3_prime_UTR_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1

Frequencies

GnomAD3 genomes AF: 0.818 AC: 118638 AN: 145086 Hom.: 48601 Cov.: 23

Gnomad AFR AF: 0.728

Gnomad AMI AF: 0.949

Gnomad AMR AF: 0.864

Gnomad ASJ AF: 0.869

Gnomad EAS AF: 0.742

Gnomad SAS AF: 0.794

Gnomad FIN AF: 0.829

Gnomad MID AF: 0.856

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.847

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.765 AC: 283 AN: 370 Hom.: 114 Cov.: 0 AF XY: 0.776 AC XY: 132 AN XY: 170

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.850 AC: 34 AN: 40

Ashkenazi Jewish (ASJ) AF: 1.00 AC: 4 AN: 4

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AF: 0.792 AC: 19 AN: 24

European-Finnish (FIN) AF: 0.864 AC: 19 AN: 22

Middle Eastern (MID) AF: 1.00 AC: 2 AN: 2

European-Non Finnish (NFE) AF: 0.752 AC: 191 AN: 254

Other (OTH) AF: 0.591 AC: 13 AN: 22

GnomAD4 genome AF: 0.818 AC: 118733 AN: 145204 Hom.: 48638 Cov.: 23 AF XY: 0.817 AC XY: 57681 AN XY: 70630

African (AFR) AF: 0.728 AC: 29279 AN: 40238

American (AMR) AF: 0.864 AC: 12621 AN: 14604

Ashkenazi Jewish (ASJ) AF: 0.869 AC: 2929 AN: 3372

East Asian (EAS) AF: 0.742 AC: 3721 AN: 5018

South Asian (SAS) AF: 0.794 AC: 3685 AN: 4642

European-Finnish (FIN) AF: 0.829 AC: 7833 AN: 9446

Middle Eastern (MID) AF: 0.853 AC: 232 AN: 272

European-Non Finnish (NFE) AF: 0.864 AC: 55914 AN: 64742

Other (OTH) AF: 0.847 AC: 1695 AN: 2002

Alfa AF: 0.724 Hom.: 2595

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Congenital myasthenic syndrome Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.7
DANN	Benign	0.52
PhyloP100		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

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: rs1053751; hg19: chr17-4801286;