17-4897993-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_153827.5(MINK1):c.*706A>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.544 in 139,842 control chromosomes in the GnomAD database, including 22,763 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.54 (22763 hom., cov: 23)
  • Exomes 𝑓: 0.30 (17 hom.)
  • Failed GnomAD Quality Control
• Consequence: MINK1 NM_153827.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.779

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

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 17-4897993-A-C is Benign according to our data. Variant chr17-4897993-A-C is described in ClinVar as [Benign]. Clinvar id is 323959.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.692 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CHRNE	NM_000080.4	c.*743T>G		3_prime_UTR_variant	12/12	ENST00000649488.2
MINK1	NM_153827.5	c.*706A>C		3_prime_UTR_variant	32/32	ENST00000355280.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MINK1	ENST00000355280.11	c.*706A>C		3_prime_UTR_variant	32/32	1	NM_153827.5	A1
CHRNE	ENST00000649488.2	c.*743T>G		3_prime_UTR_variant	12/12		NM_000080.4	P1

Frequencies

GnomAD3 genomes AF: 0.544 AC: 76053 AN: 139740 Hom.: 22754 Cov.: 23

Gnomad AFR AF: 0.274

Gnomad AMI AF: 0.763

Gnomad AMR AF: 0.554

Gnomad ASJ AF: 0.631

Gnomad EAS AF: 0.192

Gnomad SAS AF: 0.459

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.575

Gnomad NFE AF: 0.698

Gnomad OTH AF: 0.570

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.295 AC: 108 AN: 366 Hom.: 17 Cov.: 0 AF XY: 0.256 AC XY: 43 AN XY: 168

Gnomad4 AMR exome AF: 0.114

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0714

Gnomad4 FIN exome AF: 0.458

Gnomad4 NFE exome AF: 0.350

Gnomad4 OTH exome AF: 0.500

GnomAD4 genome AF: 0.544 AC: 76092 AN: 139842 Hom.: 22763 Cov.: 23 AF XY: 0.535 AC XY: 36256 AN XY: 67748

Gnomad4 AFR AF: 0.274

Gnomad4 AMR AF: 0.554

Gnomad4 ASJ AF: 0.631

Gnomad4 EAS AF: 0.193

Gnomad4 SAS AF: 0.460

Gnomad4 FIN AF: 0.644

Gnomad4 NFE AF: 0.698

Gnomad4 OTH AF: 0.571

Alfa AF: 0.636 Hom.: 19123

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myasthenic syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.89
Cadd	Benign	0.84
Dann	Benign	0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1053754; hg19: chr17-4801288;