chr3-15453922-C-G

Variant names:

• chr3-15453922-C-G
• rs140670616
• NM_005677.4:c.1205G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PP2 PP3

The NM_005677.4(COLQ):​c.1205G>C​(p.Arg402Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000687 in 1,454,868 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R402H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COLQ NM_005677.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84
• Publications: 2 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: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_005677.4
• 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, 0.817

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COLQ	NM_005677.4	c.1205G>C	p.Arg402Pro	missense_variant	Exon 16 of 17	ENST00000383788.10	NP_005668.2
COLQ	NM_080538.2	c.1175G>C	p.Arg392Pro	missense_variant	Exon 16 of 17		NP_536799.1
COLQ	NM_080539.4	c.1103G>C	p.Arg368Pro	missense_variant	Exon 15 of 16		NP_536800.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COLQ	ENST00000383788.10	c.1205G>C	p.Arg402Pro	missense_variant	Exon 16 of 17	1	NM_005677.4	ENSP00000373298.3
COLQ	ENST00000603808.5	c.1208G>C	p.Arg403Pro	missense_variant	Exon 16 of 17	1		ENSP00000474271.1
ENSG00000293553	ENST00000629729.3	n.52G>C		non_coding_transcript_exon_variant	Exon 2 of 6	5		ENSP00000518887.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.87e-7 AC: 1 AN: 1454868 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 723300

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33248

American (AMR) AF: 0.00 AC: 0 AN: 44144

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26026

East Asian (EAS) AF: 0.00 AC: 0 AN: 39260

South Asian (SAS) AF: 0.00 AC: 0 AN: 84852

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53000

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108462

Other (OTH) AF: 0.00 AC: 0 AN: 60124

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Oct 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1205G>C (p.R402P) alteration is located in exon 16 (coding exon 16) of the COLQ gene. This alteration results from a G to C substitution at nucleotide position 1205, causing the arginine (R) at amino acid position 402 to be replaced by a proline (P). 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	Pathogenic	0.57
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T;.;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.46
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Pathogenic	0.40	D
MetaRNN	Pathogenic	0.82	D;D;D;D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Uncertain	2.0	M;.;.;.
PhyloP100		1.8
PrimateAI	Benign	0.31	T
PROVEAN	Benign	-2.3	N;D;.;N
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0020	D;D;.;.
Sift4G	Uncertain	0.045	D;D;D;D
Polyphen		1.0	D;D;.;D
Vest4		0.74
MutPred		0.60		Gain of relative solvent accessibility (P = 0.1894);.;.;.;
MVP		0.97
MPC		0.14
ClinPred		0.89	D
GERP RS		4.7
Varity_R		0.41
gMVP		0.73
Mutation Taster		=60/40	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs140670616; hg19: chr3-15495429;