rs6782980

Positions:

• chr3-15458206-T-C
• chr3-15458206-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005677.4(COLQ):​c.934A>G​(p.Ser312Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,888 control chromosomes in the GnomAD database, including 1,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.049 (455 hom., cov: 32)
  • Exomes 𝑓: 0.016 (553 hom.)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.951

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0016097426).
• BP6: Variant 3-15458206-T-C is Benign according to our data. Variant chr3-15458206-T-C is described in ClinVar as [Benign]. Clinvar id is 128827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-15458206-T-C is described in Lovd as [Benign]. Variant chr3-15458206-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COLQ	NM_005677.4	c.934A>G	p.Ser312Gly	missense_variant	13/17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.904A>G	p.Ser302Gly	missense_variant	13/17		NP_536799.1
COLQ	NM_080539.4	c.832A>G	p.Ser278Gly	missense_variant	12/16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.934A>G	p.Ser312Gly	missense_variant	13/17	1	NM_005677.4	ENSP00000373298	P4

Frequencies

GnomAD3 genomes AF: 0.0494 AC: 7523 AN: 152142 Hom.: 454 Cov.: 32

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0234

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0216

Gnomad FIN AF: 0.00989

Gnomad MID AF: 0.0411

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0454

GnomAD3 exomes AF: 0.0216 AC: 5425 AN: 251474 Hom.: 202 AF XY: 0.0202 AC XY: 2750 AN XY: 135904

Gnomad AFR exome AF: 0.147

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00883

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.0256

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0122

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0160 AC: 23364 AN: 1461628 Hom.: 553 Cov.: 32 AF XY: 0.0163 AC XY: 11864 AN XY: 727122

Gnomad4 AFR exome AF: 0.149

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.0113

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0267

Gnomad4 FIN exome AF: 0.0131

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.0226

GnomAD4 genome AF: 0.0495 AC: 7535 AN: 152260 Hom.: 455 Cov.: 32 AF XY: 0.0474 AC XY: 3527 AN XY: 74452

Gnomad4 AFR AF: 0.143

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.0118

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0218

Gnomad4 FIN AF: 0.00989

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.0449

Alfa AF: 0.0202 Hom.: 226

Bravo AF: 0.0549

TwinsUK AF: 0.00863 AC: 32

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.141 AC: 623

ESP6500EA AF: 0.0138 AC: 119

ExAC AF: 0.0244 AC: 2960

Asia WGS AF: 0.0140 AC: 51 AN: 3478

EpiCase AF: 0.0150

EpiControl AF: 0.0147

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 04, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	Feb 01, 2016	- -

Congenital myasthenic syndrome 5 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, 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 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. -

not provided Benign:2

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Benign	0.20	T;.;.;.
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.36
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.65	T;T;T;T
MetaRNN	Benign	0.0016	T;T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N;.;.;.
MutationTaster	Benign	1.0	P;P;P;P;P;P;P;P
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.14	N;N;.;N
REVEL	Benign	0.17
Sift	Benign	0.32	T;T;.;.
Sift4G	Benign	0.60	T;T;T;T
Polyphen		0.0040	B;B;.;B
Vest4		0.081
MPC		0.089
ClinPred		0.0065	T
GERP RS		2.3
Varity_R		0.031
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs6782980; hg19: chr3-15499713;