Genetic Variant NM_005677.4:c.1248C>A (chr3-15453879-G-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 5P and 2B. PM1PM2PP2BP4_Moderate

The NM_005677.4(COLQ):c.1248C>A(p.Asp416Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D416D) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

COLQ
NM_005677.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.50

Publications

6 publications found

Variant links:

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: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)

COLQ links:

ENSG00000293553 (HGNC:):

ENSG00000293553 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 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.

BP4

Computational evidence support a benign effect (MetaRNN=0.23930779).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COLQ	NM_005677.4	MANE Select	c.1248C>A	p.Asp416Glu	missense	Exon 16 of 17	NP_005668.2
COLQ	NM_080538.2		c.1218C>A	p.Asp406Glu	missense	Exon 16 of 17	NP_536799.1	Q9Y215-2
COLQ	NM_080539.4		c.1146C>A	p.Asp382Glu	missense	Exon 15 of 16	NP_536800.2	Q9Y215-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COLQ	ENST00000383788.10	TSL:1 MANE Select	c.1248C>A	p.Asp416Glu	missense	Exon 16 of 17	ENSP00000373298.3	Q9Y215-1
COLQ	ENST00000603808.5	TSL:1	c.1251C>A	p.Asp417Glu	missense	Exon 16 of 17	ENSP00000474271.1	A0A0C4DGS2
ENSG00000293553	ENST00000629729.3	TSL:5	n.95C>A		non_coding_transcript_exon	Exon 2 of 6	ENSP00000518887.1	A0AAA9YHP9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

247810

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.060

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.14

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.81

M_CAP

Benign

0.032

MetaRNN

Benign

0.24

MetaSVM

Benign

-0.49

MutationAssessor

Benign

0.53

PhyloP100

2.5

PrimateAI

Benign

0.40

PROVEAN

Benign

0.11

REVEL

Benign

0.15

Sift

Benign

0.40

Sift4G

Benign

0.91

Polyphen

0.28

Vest4

0.27

MutPred

0.21

Loss of sheet (P = 0.1398)

MVP

0.95

MPC

0.091

ClinPred

0.35

GERP RS

3.4

Varity_R

0.054

gMVP

0.39

Mutation Taster

=84/16

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over