rs570601986

Variant names:

• chr17-4897956-A-AGT
• rs570601986
• ENST00000574453.5:n.*4341_*4342dupTG

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_153827.5(MINK1):​c.*673_*674dupTG variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.000808 in 144,838 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00081 (1 hom., cov: 29)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MINK1 NM_153827.5 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000808 (117/144838) while in subpopulation EAS AF = 0.0219 (104/4756). AF 95% confidence interval is 0.0185. There are 1 homozygotes in GnomAd4. There are 59 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd4 at 117 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MINK1	NM_153827.5	c.*673_*674dupTG		3_prime_UTR_variant	Exon 32 of 32	ENST00000355280.11	NP_722549.2
CHRNE	NM_000080.4	c.*778_*779dupAC		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.*673_*674dupTG		3_prime_UTR_variant	Exon 32 of 32	1	NM_153827.5	ENSP00000347427.6
CHRNE	ENST00000649488.2	c.*778_*779dupAC		3_prime_UTR_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1

Frequencies

GnomAD3 genomes AF: 0.000808 AC: 117 AN: 144726 Hom.: 1 Cov.: 29

Gnomad AFR AF: 0.000105

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000281

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0218

Gnomad SAS AF: 0.000224

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00205

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1766 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 864

African (AFR) AC: 0 AN: 0

American (AMR) AF: 0.00 AC: 0 AN: 196

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 120

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 108

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1260

Other (OTH) AF: 0.00 AC: 0 AN: 66

GnomAD4 genome AF: 0.000808 AC: 117 AN: 144838 Hom.: 1 Cov.: 29 AF XY: 0.000840 AC XY: 59 AN XY: 70250

African (AFR) AF: 0.000105 AC: 4 AN: 38216

American (AMR) AF: 0.000281 AC: 4 AN: 14244

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.0219 AC: 104 AN: 4756

South Asian (SAS) AF: 0.000224 AC: 1 AN: 4464

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9858

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 284

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66736

Other (OTH) AF: 0.00203 AC: 4 AN: 1970

Alfa AF: 0.000422 Hom.: 0

Bravo AF: 0.000892

Asia WGS AF: 0.00462 AC: 16 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital Myasthenic Syndrome, Dominant/Recessive Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.5
Mutation Taster		=100/0	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs570601986; hg19: chr17-4801251;