NM_005677.4:c.1081C>G

Variant names:

• chr3-15456013-G-C
• rs116828761
• NM_005677.4:c.1081C>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_005677.4(COLQ):​c.1081C>G​(p.Pro361Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P361S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.09
• Publications: 1 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

ENSG00000293553 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

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.1081C>G	p.Pro361Ala	missense	Exon 15 of 17	NP_005668.2
	COLQ	NM_080538.2		c.1051C>G	p.Pro351Ala	missense	Exon 15 of 17	NP_536799.1
	COLQ	NM_080539.4		c.979C>G	p.Pro327Ala	missense	Exon 14 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.1081C>G	p.Pro361Ala	missense	Exon 15 of 17	ENSP00000373298.3
	COLQ	ENST00000603808.5	TSL:1	c.1081C>G	p.Pro361Ala	missense	Exon 15 of 17	ENSP00000474271.1
	COLQ	ENST00000874202.1		c.1096C>G	p.Pro366Ala	missense	Exon 15 of 17	ENSP00000544261.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.37	T
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.27	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Pathogenic	0.79	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		9.1
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-2.0	N
REVEL	Pathogenic	0.80
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.022	D
Polyphen		0.98	D
Vest4		0.83
MutPred		0.54		Gain of catalytic residue at P361 (P = 0.0118)
MVP		0.98
MPC		0.094
ClinPred		0.91	D
GERP RS		5.8
Varity_R		0.25
gMVP		0.60
Mutation Taster		=25/75	disease causing

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: rs116828761; hg19: chr3-15497520;