ENST00000574453.5:n.*4211C>G

Variant names:

• chr17-4897830-C-G
• rs9914357
• ENST00000574453.5:n.*4211C>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The ENST00000574453.5(MINK1):​n.*4211C>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 0.152 in 151,546 control chromosomes in the GnomAD database, including 2,825 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2825 hom., cov: 30)
  • Exomes 𝑓: 0.046 (0 hom.)
• Consequence: MINK1 ENST00000574453.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.501
• Publications: 6 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 17-4897830-C-G is Benign according to our data. Variant chr17-4897830-C-G is described in ClinVar as [Benign]. Clinvar id is 323943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.322 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MINK1	NM_153827.5	c.*543C>G		3_prime_UTR_variant	Exon 32 of 32	ENST00000355280.11	NP_722549.2
CHRNE	NM_000080.4	c.*906G>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.*543C>G		3_prime_UTR_variant	Exon 32 of 32	1	NM_153827.5	ENSP00000347427.6
CHRNE	ENST00000649488.2	c.*906G>C		3_prime_UTR_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1

Frequencies

GnomAD3 genomes AF: 0.153 AC: 23026 AN: 150890 Hom.: 2814 Cov.: 30

Gnomad AFR AF: 0.313

Gnomad AMI AF: 0.0662

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.0624

Gnomad EAS AF: 0.336

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.0715

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0619

Gnomad OTH AF: 0.126

GnomAD4 exome AF: 0.0465 AC: 25 AN: 538 Hom.: 0 Cov.: 0 AF XY: 0.0617 AC XY: 19 AN XY: 308

African (AFR) AF: 0.500 AC: 2 AN: 4

American (AMR) AF: 0.250 AC: 1 AN: 4

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.250 AC: 1 AN: 4

South Asian (SAS) AF: 0.00 AC: 0 AN: 36

European-Finnish (FIN) AF: 0.0619 AC: 13 AN: 210

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

European-Non Finnish (NFE) AF: 0.0296 AC: 8 AN: 270

Other (OTH) AF: 0.00 AC: 0 AN: 8

GnomAD4 genome AF: 0.153 AC: 23076 AN: 151008 Hom.: 2825 Cov.: 30 AF XY: 0.154 AC XY: 11333 AN XY: 73802

African (AFR) AF: 0.314 AC: 12810 AN: 40838

American (AMR) AF: 0.169 AC: 2570 AN: 15210

Ashkenazi Jewish (ASJ) AF: 0.0624 AC: 216 AN: 3460

East Asian (EAS) AF: 0.335 AC: 1705 AN: 5086

South Asian (SAS) AF: 0.101 AC: 483 AN: 4796

European-Finnish (FIN) AF: 0.0715 AC: 750 AN: 10496

Middle Eastern (MID) AF: 0.0850 AC: 25 AN: 294

European-Non Finnish (NFE) AF: 0.0618 AC: 4195 AN: 67828

Other (OTH) AF: 0.125 AC: 262 AN: 2094

Alfa AF: 0.0426 Hom.: 50

Bravo AF: 0.172

Asia WGS AF: 0.196 AC: 680 AN: 3476

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	-0.25
CADD	Benign	13
DANN	Benign	0.86
PhyloP100		0.50
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
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: rs9914357; hg19: chr17-4801125;