chr3-15478979-T-C

Position:

chr3-15478979-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005677.4(COLQ):c.391A>G(p.Lys131Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000339 in 1,614,164 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00034 ( 0 hom. )

Consequence

COLQ
NM_005677.4 missense, splice_region

Scores

Splicing: ADA: 0.02528

Clinical Significance

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

Conservation

PhyloP100: 4.72

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:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.21136287).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COLQ	NM_005677.4 linkuse as main transcript	c.391A>G	p.Lys131Glu	missense_variant, splice_region_variant	5/17	ENST00000383788.10
COLQ	NM_080538.2 linkuse as main transcript	c.361A>G	p.Lys121Glu	missense_variant, splice_region_variant	5/17
COLQ	NM_080539.4 linkuse as main transcript	c.289A>G	p.Lys97Glu	missense_variant, splice_region_variant	4/16

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COLQ	ENST00000383788.10 linkuse as main transcript	c.391A>G	p.Lys131Glu	missense_variant, splice_region_variant	5/17	1	NM_005677.4	P4	Q9Y215-1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152154

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

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:

0.0000942

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.000957

GnomAD3 exomes

AF:

0.000247

AC:

AN:

251354

Hom.:

AF XY:

0.000258

AC XY:

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000277

Gnomad NFE exome

AF:

0.000422

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000340

AC:

497

AN:

1461892

Hom.:

Cov.:

AF XY:

0.000338

AC XY:

246

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.000134

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000393

Gnomad4 NFE exome

AF:

0.000404

Gnomad4 OTH exome

AF:

0.000298

GnomAD4 genome

AF:

0.000335

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.000282

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.000120

Gnomad4 AMR

AF:

0.000262

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000573

Gnomad4 OTH

AF:

0.000947

Alfa

AF:

0.000479

Hom.:

Bravo

AF:

0.000261

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000465

AC:

ExAC

AF:

0.000181

AC:

EpiCase

AF:

0.000545

EpiControl

AF:

0.000474

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	Baylor Genetics	Aug 14, 2018	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 14, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 23, 2022	This sequence change replaces lysine, which is basic and polar, with glutamic acid, which is acidic and polar, at codon 131 of the COLQ protein (p.Lys131Glu). This variant is present in population databases (rs142980906, gnomAD 0.04%). 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: 197779). 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 C55"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 20, 2015	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.62

BayesDel_addAF

Benign

-0.048

BayesDel_noAF

Uncertain

0.020

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.29

T;.;.;.;.

Eigen

Uncertain

0.50

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.97

LIST_S2

Uncertain

0.93

D;D;D;T;T

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.21

T;T;T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.5

L;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-1.2

N;N;.;N;.

REVEL

Uncertain

0.61

Sift

Benign

0.051

T;D;.;.;.

Sift4G

Benign

0.20

T;T;T;T;T

Polyphen

0.99

D;D;.;D;.

Vest4

0.65

MVP

0.91

MPC

0.14

ClinPred

0.059

GERP RS

5.3

Varity_R

0.39

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.025

dbscSNV1_RF

Benign

0.20

SpliceAI score (max)

0.31

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.31

Position offset: -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