3-15470613-C-T

Variant names:

• chr3-15470613-C-T
• rs104893733
• NM_005677.4:c.640G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_005677.4(COLQ):​c.640G>A​(p.Glu214Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.65
• Publications: 0 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: Uncertain_significance. The variant received 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLQ	NM_005677.4	c.640G>A	p.Glu214Lys	missense_variant	Exon 11 of 17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.610G>A	p.Glu204Lys	missense_variant	Exon 11 of 17		NP_536799.1
COLQ	NM_080539.4	c.538G>A	p.Glu180Lys	missense_variant	Exon 10 of 16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.640G>A	p.Glu214Lys	missense_variant	Exon 11 of 17	1	NM_005677.4	ENSP00000373298.3
COLQ	ENST00000603808.5	c.640G>A	p.Glu214Lys	missense_variant	Exon 11 of 17	1		ENSP00000474271.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Jul 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.640G>A (p.E214K) alteration is located in exon 11 (coding exon 11) of the COLQ gene. This alteration results from a G to A substitution at nucleotide position 640, causing the glutamic acid (E) at amino acid position 214 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.53
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T;.;.;.;.
Eigen	Pathogenic	0.71
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.93	D;D;D;T;D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.73	D;D;D;D;D
MetaSVM	Pathogenic	0.91	D
MutationAssessor	Uncertain	2.2	M;.;.;.;.
PhyloP100		6.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-2.4	N;N;.;N;.
REVEL	Uncertain	0.63
Sift	Benign	0.055	T;T;.;.;.
Sift4G	Benign	0.18	T;T;T;T;T
Polyphen		1.0	D;D;.;D;.
Vest4		0.89
MutPred		0.39		Gain of MoRF binding (P = 0.0061);.;Gain of MoRF binding (P = 0.0061);.;.;
MVP		0.94
MPC		0.11
ClinPred		0.97	D
GERP RS		6.0
Varity_R		0.39
gMVP		0.48
Mutation Taster		=52/48	polymorphism

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: rs104893733; hg19: chr3-15512120;