rs7774

Variant names:

• chr17-4897868-C-A
• rs7774
• ENST00000574453.5:n.*4249C>A

Your query was ambiguous. Multiple possible variants found:

• chr17-4897868-C-A
• chr17-4897868-C-G
• chr17-4897868-C-T

Variant summary

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

The NM_153827.5(MINK1):​c.*581C>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 149,182 control chromosomes in the GnomAD database, including 10,488 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.37 (10451 hom., cov: 25)
  • Exomes 𝑓: 0.32 (37 hom.)
• Consequence: MINK1 NM_153827.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.73
• Publications: 13 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=-0.98).
• BP6: Variant 17-4897868-C-A is Benign according to our data. Variant chr17-4897868-C-A is described in ClinVar as [Benign]. Clinvar id is 323948.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MINK1	NM_153827.5	c.*581C>A		3_prime_UTR_variant	Exon 32 of 32	ENST00000355280.11	NP_722549.2
CHRNE	NM_000080.4	c.*868G>T		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.*581C>A		3_prime_UTR_variant	Exon 32 of 32	1	NM_153827.5	ENSP00000347427.6
CHRNE	ENST00000649488.2	c.*868G>T		3_prime_UTR_variant	Exon 12 of 12		NM_000080.4	ENSP00000497829.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 55168 AN: 148516 Hom.: 10439 Cov.: 25

Gnomad AFR AF: 0.400

Gnomad AMI AF: 0.296

Gnomad AMR AF: 0.365

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.551

Gnomad SAS AF: 0.580

Gnomad FIN AF: 0.414

Gnomad MID AF: 0.407

Gnomad NFE AF: 0.323

Gnomad OTH AF: 0.356

GnomAD4 exome AF: 0.316 AC: 173 AN: 548 Hom.: 37 Cov.: 0 AF XY: 0.281 AC XY: 86 AN XY: 306

African (AFR) AF: 0.00 AC: 0 AN: 4

American (AMR) AF: 0.500 AC: 1 AN: 2

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AF: 0.594 AC: 19 AN: 32

European-Finnish (FIN) AF: 0.401 AC: 89 AN: 222

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.225 AC: 63 AN: 280

Other (OTH) AF: 0.125 AC: 1 AN: 8

GnomAD4 genome AF: 0.372 AC: 55225 AN: 148634 Hom.: 10451 Cov.: 25 AF XY: 0.381 AC XY: 27596 AN XY: 72364

African (AFR) AF: 0.400 AC: 16084 AN: 40176

American (AMR) AF: 0.365 AC: 5474 AN: 15012

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1309 AN: 3446

East Asian (EAS) AF: 0.551 AC: 2717 AN: 4928

South Asian (SAS) AF: 0.579 AC: 2656 AN: 4584

European-Finnish (FIN) AF: 0.414 AC: 4154 AN: 10024

Middle Eastern (MID) AF: 0.390 AC: 113 AN: 290

European-Non Finnish (NFE) AF: 0.323 AC: 21719 AN: 67200

Other (OTH) AF: 0.353 AC: 733 AN: 2074

Alfa AF: 0.312 Hom.: 2944

Asia WGS AF: 0.563 AC: 1956 AN: 3478

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	-0.98
CADD	Benign	0.042
DANN	Benign	0.33
PhyloP100		-2.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs7774; hg19: chr17-4801163; COSMIC: COSV53418092; COSMIC: COSV53418092;