rs146619514

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005677.4(COLQ):c.788C>T(p.Pro263Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000258 in 1,613,976 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00027 ( 0 hom. )

Consequence

COLQ
NM_005677.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.42

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 links:

COLQ (HGNC:):

COLQ links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COLQ	NM_005677.4 linkuse as main transcript	c.788C>T	p.Pro263Leu	missense_variant	12/17	ENST00000383788.10	NP_005668.2	Q9Y215-1
COLQ	NM_080538.2 linkuse as main transcript	c.758C>T	p.Pro253Leu	missense_variant	12/17		NP_536799.1	Q9Y215-2
COLQ	NM_080539.4 linkuse as main transcript	c.686C>T	p.Pro229Leu	missense_variant	11/16		NP_536800.2	Q9Y215-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10 linkuse as main transcript	c.788C>T	p.Pro263Leu	missense_variant	12/17	1	NM_005677.4	ENSP00000373298.3		Q9Y215-1
COLQ	ENST00000603808.5 linkuse as main transcript	c.788C>T	p.Pro263Leu	missense_variant	12/17	1		ENSP00000474271.1		A0A0C4DGS2

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000105

AC:

AN:

247530

Hom.:

AF XY:

0.000119

AC XY:

AN XY:

134356

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000145

Gnomad OTH exome

AF:

0.000329

GnomAD4 exome

AF:

0.000270

AC:

394

AN:

1461748

Hom.:

Cov.:

AF XY:

0.000267

AC XY:

194

AN XY:

727174

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.0000348

Gnomad4 FIN exome

AF:

0.0000188

Gnomad4 NFE exome

AF:

0.000335

Gnomad4 OTH exome

AF:

0.000149

GnomAD4 genome

AF:

0.000145

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000108

AC XY:

AN XY:

74374

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.000478

Alfa

AF:

0.000232

Hom.:

Bravo

AF:

0.000144

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000296

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Congenital myasthenic syndrome 5

Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 18, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 263 of the COLQ protein (p.Pro263Leu). This variant is present in population databases (rs146619514, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COLQ-related conditions. ClinVar contains an entry for this variant (Variation ID: 343849). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jul 23, 2019	This variant was identified as homozygous -
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 08, 2024

The c.788C>T (p.P263L) alteration is located in exon 12 (coding exon 12) of the COLQ gene. This alteration results from a C to T substitution at nucleotide position 788, causing the proline (P) at amino acid position 263 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Sep 01, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Benign

-0.0061

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.47

T;.;.;.

Eigen

Benign

0.064

Eigen_PC

Benign

-0.018

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Pathogenic

0.37

MetaRNN

Uncertain

0.67

D;D;D;D

MetaSVM

Pathogenic

0.84

MutationAssessor

Uncertain

2.8

M;.;.;.

PrimateAI

Benign

0.35

PROVEAN

Benign

-2.3

N;N;.;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.019

D;D;.;.

Sift4G

Uncertain

0.013

D;D;D;D

Polyphen

1.0

D;D;.;D

Vest4

0.33

MVP

0.95

MPC

0.10

ClinPred

0.27

GERP RS

3.7

Varity_R

0.069

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over