Genetic Variant COLQ:p.Glu214Lys (chr3-15470613-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP2

The NM_005677.4(COLQ):c.640G>A(p.Glu214Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

COLQ
NM_005677.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.65

Publications

0 publications found

Variant links:

Genes affected

COLQ (HGNC:2226): (collagen like tail subunit of asymmetric acetylcholinesterase) This gene encodes the subunit of a collagen-like molecule associated with acetylcholinesterase in skeletal muscle. Each molecule is composed of three identical subunits. Each subunit contains a proline-rich attachment domain (PRAD) that binds an acetylcholinesterase tetramer to anchor the catalytic subunit of the enzyme to the basal lamina. Mutations in this gene are associated with endplate acetylcholinesterase deficiency. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

COLQ Gene-Disease associations (from GenCC):

congenital myasthenic syndrome 5
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, PanelApp Australia

COLQ links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 16 curated pathogenic missense variants (we use a threshold of 10). The gene has 5 curated benign missense variants. Gene score misZ: -0.21928 (below the threshold of 3.09). Trascript score misZ: -0.17745 (below the threshold of 3.09). GenCC associations: The gene is linked to congenital myasthenic syndrome 5.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005677.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COLQ	NM_005677.4	MANE Select	c.640G>A	p.Glu214Lys	missense	Exon 11 of 17	NP_005668.2
COLQ	NM_080538.2		c.610G>A	p.Glu204Lys	missense	Exon 11 of 17	NP_536799.1
COLQ	NM_080539.4		c.538G>A	p.Glu180Lys	missense	Exon 10 of 16	NP_536800.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COLQ	ENST00000383788.10	TSL:1 MANE Select	c.640G>A	p.Glu214Lys	missense	Exon 11 of 17	ENSP00000373298.3
COLQ	ENST00000603808.5	TSL:1	c.640G>A	p.Glu214Lys	missense	Exon 11 of 17	ENSP00000474271.1
COLQ	ENST00000383781.8	TSL:5	c.610G>A	p.Glu204Lys	missense	Exon 11 of 17	ENSP00000373291.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.640G>A (p.E214K) alteration is located in exon 11 (coding exon 11) of the COLQ gene. This alteration results from a G to A substitution at nucleotide position 640, causing the glutamic acid (E) at amino acid position 214 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.47

Eigen

Pathogenic

0.71

Eigen_PC

Pathogenic

0.75

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.12

MetaRNN

Uncertain

0.73

MetaSVM

Pathogenic

0.91

MutationAssessor

Uncertain

2.2

PhyloP100

6.6

PrimateAI

Pathogenic

0.81

PROVEAN

Uncertain

-2.4

REVEL

Uncertain

0.63

Sift

Benign

0.055

Sift4G

Benign

0.18

Polyphen

1.0

Vest4

0.89

MutPred

0.39

Gain of MoRF binding (P = 0.0061)

MVP

0.94

MPC

0.11

ClinPred

0.97

GERP RS

6.0

Varity_R

0.39

gMVP

0.48

Mutation Taster

=52/48

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over