rs1042644306

chr2-189068815-G-Achr2-189068815-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP6

The NM_000393.5(COL5A2):c.1228C>T(p.Pro410Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P410L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.45

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, COL5A2
• BP6: Variant 2-189068815-G-A is Benign according to our data. Variant chr2-189068815-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 392252.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.1228C>T	p.Pro410Ser	missense_variant	19/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.1090C>T	p.Pro364Ser	missense_variant	22/57
COL5A2	XM_047443251.1	c.1090C>T	p.Pro364Ser	missense_variant	24/59
COL5A2	XM_047443252.1	c.1090C>T	p.Pro364Ser	missense_variant	23/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.1228C>T	p.Pro410Ser	missense_variant	19/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.359-2382C>T		intron_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250512 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135556

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jan 09, 2017

A variant of uncertain significance has been identified in the COL5A2 gene. The P410S variant has not been published as a pathogenic variant or been reported as a benign variant to our knowledge. This variant was not observed in the Exome Aggregation Consortium or in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The P410S variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. Additionally, this substitution occurs at a position that is conserved in mammals. Furthermore, in silico analysis predicts this variant is probably damaging to the protein structure/function. Nevertheless, the P410S variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of pathogenic missense variants occur (Stenson et al., 2014; Symoens et al., 2012). However, in contrast to several other collagen genes, relatively few pathogenic Glycine substitutions have been reported in COL5A2 in association with EDS. Most pathogenic variants in COL5A2 are in-frame splice site changes that cause exon skipping (Symoens et al., 2012). -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jul 05, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
Cadd	Benign	22
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.4	L;L
MutationTaster	Benign	0.68	D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.40
Sift	Benign	0.071	T;.
Sift4G	Benign	0.19	T;.
Polyphen		0.21	B;B
Vest4		0.25
MutPred		0.36		Gain of phosphorylation at P410 (P = 0.0102);Gain of phosphorylation at P410 (P = 0.0102);
MVP		0.67
MPC		0.30
ClinPred		0.41	T
GERP RS		5.7
Varity_R		0.050
gMVP		0.16

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

LitVar

Other links and lift over

dbSNP: rs1042644306; hg19: chr2-189933541;