rs141210030

Positions:

• chr2-189053902-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PP2 PP3 BP4 BP6 BS2

The NM_000393.5(COL5A2):​c.2492G>C​(p.Gly831Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000886 in 1,613,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G831G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00036 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:2
• Conservation: PhyloP100: 6.05

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_benign. Variant got -4 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• PP3: Multiple lines of computational evidence support a deleterious effect 7: BayesDel_addAF, BayesDel_noAF, Eigen, MutationAssessor, PrimateAI, PROVEAN, REVEL [when AlphaMissense, max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.41920644).
• BP6: Variant 2-189053902-C-G is Benign according to our data. Variant chr2-189053902-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 255998.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS2: High AC in GnomAd4 at 55 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.2492G>C	p.Gly831Ala	missense_variant	37/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.2354G>C	p.Gly785Ala	missense_variant	40/57
COL5A2	XM_047443251.1	c.2354G>C	p.Gly785Ala	missense_variant	42/59
COL5A2	XM_047443252.1	c.2354G>C	p.Gly785Ala	missense_variant	41/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.2492G>C	p.Gly831Ala	missense_variant	37/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.1331G>C	p.Gly444Ala	missense_variant	30/47	5

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152100 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00106

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000996 AC: 25 AN: 250992 Hom.: 0 AF XY: 0.0000811 AC XY: 11 AN XY: 135688

Gnomad AFR exome AF: 0.00111

Gnomad AMR exome AF: 0.0000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000655

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000602 AC: 88 AN: 1461300 Hom.: 0 Cov.: 31 AF XY: 0.0000564 AC XY: 41 AN XY: 727004

Gnomad4 AFR exome AF: 0.00152

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000928

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.000298

GnomAD4 genome AF: 0.000361 AC: 55 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.000376 AC XY: 28 AN XY: 74436

Gnomad4 AFR AF: 0.00108

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000178 Hom.: 0

Bravo AF: 0.000363

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000988 AC: 12

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 16, 2023	BS1, PP3, PM1 -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Dec 08, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Reported in ClinVar (ClinVar Variant ID# 255998; Landrum et al., 2016); This variant is associated with the following publications: (PMID: 22696272, 24077912) -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The p.G831A variant (also known as c.2492G>C), located in coding exon 37 of the COL5A2 gene, results from a G to C substitution at nucleotide position 2492. The glycine at codon 831 is replaced by alanine, an amino acid with similar properties. Internal structural analysis indicates that this alteration disrupts the characteristic G-X-Y motif of the triple helical domain in the COL5A2 protein and inserts a bulky side chain into a sterically-constrained region (Bella J et al. Science. 1994;266:75-81; Hohenester E et al. Proc. Natl. Acad. Sci.U.S.A. 2008;105:18273-7; Ambry internal data). Glycine substitutions in the triple helical domain of COL5A2 have been reported in association with classic Ehlers-Danlos syndrome (cEDS), but the number of affected individuals is limited and several other COL5A2 glycine substitutions in the triple helical domain (e.g., p.G951E and p.G831A) are too common for disease in population databases (Symoens S et al. Hum. Mutat., 2012 Oct;33:1485-93; Ritelli M et al. Orphanet J Rare Dis. 2013 Apr;8:58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 09, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Pathogenic	0.55
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.81	D;T;D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.42	T;T;T
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.;H
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.0	D;.;.
REVEL	Pathogenic	0.88
Sift	Benign	0.041	D;.;.
Sift4G	Uncertain	0.036	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.79
MVP		0.97
MPC		0.28
ClinPred		0.87	D
GERP RS		5.9
Varity_R		0.37
gMVP		0.95

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: rs141210030; hg19: chr2-189918628;