rs121912930

Positions:

• chr2-189043177-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_000393.5(COL5A2):​c.3445G>C​(p.Gly1149Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.88

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 Likely_pathogenic. Variant got 9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A2. . Gene score misZ 2.4395 (greater than the threshold 3.09). Trascript score misZ 3.3523 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987
• PP5: Variant 2-189043177-C-G is Pathogenic according to our data. Variant chr2-189043177-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17198.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.3445G>C	p.Gly1149Arg	missense_variant	48/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.3307G>C	p.Gly1103Arg	missense_variant	51/57		XP_011508875.1
COL5A2	XM_047443251.1	c.3307G>C	p.Gly1103Arg	missense_variant	53/59		XP_047299207.1
COL5A2	XM_047443252.1	c.3307G>C	p.Gly1103Arg	missense_variant	52/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.3445G>C	p.Gly1149Arg	missense_variant	48/54	1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.2284G>C	p.Gly762Arg	missense_variant	41/47	5		ENSP00000482184

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, classic type Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Oct 01, 1998

- -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 13, 2022

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt COL5A2 protein function. ClinVar contains an entry for this variant (Variation ID: 17198). This missense change has been observed in individual(s) with Ehlers-Danlos syndrome (PMID: 9783710). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs121912930, gnomAD 0.0009%). This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 1149 of the COL5A2 protein (p.Gly1149Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;T;D
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	.;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.93	D
MutationAssessor	Pathogenic	4.5	H;.;H
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.94	D
PROVEAN	Pathogenic	-7.7	D;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.97
MutPred		0.99		Gain of MoRF binding (P = 0.0139);.;Gain of MoRF binding (P = 0.0139);
MVP		0.99
MPC		0.31
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.97
gMVP		0.99

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: rs121912930; hg19: chr2-189907903;