Genetic Variant COL5A2:p.Thr988Lys (chr2-189050645-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1PM2

The NM_000393.5(COL5A2):c.2963C>A(p.Thr988Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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. T988M) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.82

Publications

3 publications found

Variant links:

Genes affected

COL5A2 (HGNC:2210): (collagen type V alpha 2 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. [provided by RefSeq, Jul 2008]

COL5A2 Gene-Disease associations (from GenCC):

Ehlers-Danlos syndrome
Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
Ehlers-Danlos syndrome, classic type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
Ehlers-Danlos syndrome, classic type, 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

COL5A2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000393.5

PM2

Very rare variant in population databases, with high coverage;

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000393.5. 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
	COL5A2	NM_000393.5	MANE Select	c.2963C>A	p.Thr988Lys	missense	Exon 43 of 54	NP_000384.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.2963C>A	p.Thr988Lys	missense	Exon 43 of 54	ENSP00000364000.3
COL5A2	ENST00000858728.1		c.2960C>A	p.Thr987Lys	missense	Exon 43 of 54	ENSP00000528787.1
COL5A2	ENST00000858729.1		c.2963C>A	p.Thr988Lys	missense	Exon 43 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.85

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Uncertain

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.43

Eigen

Uncertain

0.55

Eigen_PC

Uncertain

0.60

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.063

MetaRNN

Uncertain

0.60

MetaSVM

Uncertain

0.61

MutationAssessor

Benign

0.49

PhyloP100

5.8

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-2.1

REVEL

Uncertain

0.54

Sift

Benign

0.051

Sift4G

Benign

0.93

Polyphen

1.0

Vest4

0.64

MutPred

0.45

Gain of methylation at T988 (P = 0.0051)

MVP

0.84

MPC

0.31

ClinPred

0.63

GERP RS

6.0

Varity_R

0.11

gMVP

0.42

Mutation Taster

=59/41

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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