chr3-15458206-T-C

Variant names:

• chr3-15458206-T-C
• rs6782980
• NM_005677.4:c.934A>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 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. 16/21 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
• Publications: 7 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• 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.
• 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 VariationId is 128827.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COLQ	NM_005677.4	MANE Select	c.934A>G	p.Ser312Gly	missense	Exon 13 of 17	NP_005668.2
	COLQ	NM_080538.2		c.904A>G	p.Ser302Gly	missense	Exon 13 of 17	NP_536799.1
	COLQ	NM_080539.4		c.832A>G	p.Ser278Gly	missense	Exon 12 of 16	NP_536800.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COLQ	ENST00000383788.10	TSL:1 MANE Select	c.934A>G	p.Ser312Gly	missense	Exon 13 of 17	ENSP00000373298.3
	COLQ	ENST00000603808.5	TSL:1	c.934A>G	p.Ser312Gly	missense	Exon 13 of 17	ENSP00000474271.1
	COLQ	ENST00000874202.1		c.949A>G	p.Ser317Gly	missense	Exon 13 of 17	ENSP00000544261.1

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

GnomAD2 exomes AF: 0.0216 AC: 5425 AN: 251474 AF XY: 0.0202

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 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

African (AFR) AF: 0.149 AC: 4977 AN: 33474

American (AMR) AF: 0.0132 AC: 589 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 295 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0267 AC: 2305 AN: 86240

European-Finnish (FIN) AF: 0.0131 AC: 699 AN: 53418

Middle Eastern (MID) AF: 0.0412 AC: 230 AN: 5586

European-Non Finnish (NFE) AF: 0.0116 AC: 12901 AN: 1111992

Other (OTH) AF: 0.0226 AC: 1367 AN: 60364

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

African (AFR) AF: 0.143 AC: 5919 AN: 41530

American (AMR) AF: 0.0233 AC: 357 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.0218 AC: 105 AN: 4820

European-Finnish (FIN) AF: 0.00989 AC: 105 AN: 10612

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 901 AN: 68034

Other (OTH) AF: 0.0449 AC: 95 AN: 2114

Alfa AF: 0.0266 Hom.: 506

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

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Congenital myasthenic syndrome 5 (2)
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

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
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.20	N
PhyloP100		0.95
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.14	N
REVEL	Benign	0.17
Sift	Benign	0.32	T
Sift4G	Benign	0.60	T
Polyphen		0.0040	B
Vest4		0.081
MPC		0.089
ClinPred		0.0065	T
GERP RS		2.3
Varity_R		0.031
gMVP		0.25
Mutation Taster		=96/4	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: rs6782980; hg19: chr3-15499713;