NM_005677.4:c.72G>A

Variant names:

• chr3-15521554-C-T
• rs111339593
• NM_005677.4:c.72G>A

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005677.4(COLQ):​c.72G>A​(p.Pro24Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00015 in 1,614,128 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. P24P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00074 (2 hom., cov: 32)
  • Exomes 𝑓: 0.000088 (0 hom.)
• Consequence: COLQ NM_005677.4 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.976
• 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-15521554-C-T is Benign according to our data. Variant chr3-15521554-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 259863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.976 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000742 (113/152248) while in subpopulation AFR AF = 0.00224 (93/41536). AF 95% confidence interval is 0.00187. There are 2 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

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.72G>A	p.Pro24Pro	synonymous	Exon 1 of 17	NP_005668.2
	COLQ	NM_080539.4		c.72G>A	p.Pro24Pro	synonymous	Exon 1 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.72G>A	p.Pro24Pro	synonymous	Exon 1 of 17	ENSP00000373298.3
	COLQ	ENST00000603808.5	TSL:1	c.72G>A	p.Pro24Pro	synonymous	Exon 1 of 17	ENSP00000474271.1
	COLQ	ENST00000874202.1		c.72G>A	p.Pro24Pro	synonymous	Exon 1 of 17	ENSP00000544261.1

Frequencies

GnomAD3 genomes AF: 0.000677 AC: 103 AN: 152130 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00200

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.000175 AC: 44 AN: 251462 AF XY: 0.000110

Gnomad AFR exome AF: 0.00209

Gnomad AMR exome AF: 0.000173

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000882 AC: 129 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000770 AC XY: 56 AN XY: 727242

African (AFR) AF: 0.00266 AC: 89 AN: 33480

American (AMR) AF: 0.000179 AC: 8 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1112010

Other (OTH) AF: 0.000199 AC: 12 AN: 60396

GnomAD4 genome AF: 0.000742 AC: 113 AN: 152248 Hom.: 2 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74432

African (AFR) AF: 0.00224 AC: 93 AN: 41536

American (AMR) AF: 0.00111 AC: 17 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.000198 Hom.: 0

Bravo AF: 0.000786

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Congenital myasthenic syndrome 5 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.6
DANN	Benign	0.37
PhyloP100		-0.98
PromoterAI		-0.16	Neutral

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: rs111339593; hg19: chr3-15563061; COSMIC: COSV67526626;