NM_000393.5:c.754G>T

Variant names:

• chr2-189085204-C-A
• rs1553517323
• NM_000393.5:c.754G>T

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_000393.5(COL5A2):​c.754G>T​(p.Gly252Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000686 in 1,458,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 5.66
• Publications: 0 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.99
• PP5: Variant 2-189085204-C-A is Pathogenic according to our data. Variant chr2-189085204-C-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 523366.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.754G>T	p.Gly252Cys	missense_variant	Exon 11 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.616G>T	p.Gly206Cys	missense_variant	Exon 14 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.616G>T	p.Gly206Cys	missense_variant	Exon 16 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.616G>T	p.Gly206Cys	missense_variant	Exon 15 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.754G>T	p.Gly252Cys	missense_variant	Exon 11 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.124G>T	p.Gly42Cys	missense_variant	Exon 11 of 47	5		ENSP00000482184.1
COL5A2	ENST00000649966.1	c.616G>T	p.Gly206Cys	missense_variant	Exon 11 of 11			ENSP00000496785.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1458708 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 725390

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.00 AC: 0 AN: 44352

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25994

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85630

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53240

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110374

Other (OTH) AF: 0.00 AC: 0 AN: 60284

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hyperextensible skin;C0423113:Telecanthus;C1844820:Joint hypermobility;C5702564:Neuropathic spinal arthropathy Pathogenic:1

Jan 01, 2017

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 2 Pathogenic:1

May 28, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Jul 03, 2019

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has been observed to be de novo in an individual with clinical features of connective tissue disease (Invitae). ClinVar contains an entry for this variant (Variation ID: 523366). This variant is not present in population databases (ExAC no frequency). This sequence change replaces glycine with cysteine at codon 252 of the COL5A2 protein (p.Gly252Cys). The glycine residue is highly conserved and there is a large physicochemical difference between glycine and cysteine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	D;T;D;.
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.90	.;D;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Pathogenic	0.96	D
MutationAssessor	Pathogenic	4.1	H;.;H;.
PhyloP100		5.7
PrimateAI	Uncertain	0.75	T
PROVEAN	Pathogenic	-6.8	D;.;.;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.;.;.
Sift4G	Pathogenic	0.0010	D;D;.;.
Polyphen		1.0	D;.;D;.
Vest4		0.97
MutPred		0.99		Gain of catalytic residue at G252 (P = 0.0367);.;Gain of catalytic residue at G252 (P = 0.0367);.;
MVP		0.98
MPC		0.95
ClinPred		1.0	D
GERP RS		6.0
Varity_R		0.84
gMVP		0.99
Mutation Taster		=47/53	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs1553517323; hg19: chr2-189949930;