rs1060501908

Positions:

• chr2-189079983-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000393.5(COL5A2):​c.955T>C​(p.Ser319Pro) 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. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.911

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 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.113250524).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.955T>C	p.Ser319Pro	missense_variant	14/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.817T>C	p.Ser273Pro	missense_variant	17/57
COL5A2	XM_047443251.1	c.817T>C	p.Ser273Pro	missense_variant	19/59
COL5A2	XM_047443252.1	c.817T>C	p.Ser273Pro	missense_variant	18/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.955T>C	p.Ser319Pro	missense_variant	14/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.325T>C	p.Ser109Pro	missense_variant	14/47	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 19, 2022

This sequence change replaces serine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 319 of the COL5A2 protein (p.Ser319Pro). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408294). 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 not expected to disrupt COL5A2 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Benign	0.67
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.47
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.55	N;.;N
MutationTaster	Benign	0.83	D
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	0.23	N;.;.
REVEL	Benign	0.14
Sift	Benign	0.50	T;.;.
Sift4G	Benign	0.56	T;T;.
Polyphen		0.0	B;.;B
Vest4		0.13
MutPred		0.20		Loss of phosphorylation at S319 (P = 0.0129);.;Loss of phosphorylation at S319 (P = 0.0129);
MVP		0.32
MPC		0.80
ClinPred		0.32	T
GERP RS		1.2
Varity_R		0.042
gMVP		0.41

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: rs1060501908; hg19: chr2-189944709;