rs768663426

chr2-189048241-T-C

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_000393.5(COL5A2):c.3169A>G(p.Thr1057Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1057N) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 0.852

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 -1 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.120990515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.3169A>G	p.Thr1057Ala	missense_variant	45/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.3031A>G	p.Thr1011Ala	missense_variant	48/57
COL5A2	XM_047443251.1	c.3031A>G	p.Thr1011Ala	missense_variant	50/59
COL5A2	XM_047443252.1	c.3031A>G	p.Thr1011Ala	missense_variant	49/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.3169A>G	p.Thr1057Ala	missense_variant	45/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.2008A>G	p.Thr670Ala	missense_variant	38/47	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251302 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135834

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: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461732 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727180

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000894

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000450

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2018

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 07, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Sep 25, 2022

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. 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. ClinVar contains an entry for this variant (Variation ID: 577774). This variant has not been reported in the literature in individuals affected with COL5A2-related conditions. This variant is present in population databases (rs768663426, gnomAD 0.002%). This sequence change replaces threonine, which is neutral and polar, with alanine, which is neutral and non-polar, at codon 1057 of the COL5A2 protein (p.Thr1057Ala). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.16
Cadd	Benign	20
Dann	Benign	0.92
DEOGEN2	Benign	0.16	T;T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.25
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.085	N;.;N
MutationTaster	Benign	0.51	N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.11	N;.;.
REVEL	Benign	0.29
Sift	Benign	0.33	T;.;.
Sift4G	Benign	0.51	T;T;.
Polyphen		0.011	B;.;B
Vest4		0.39
MutPred		0.24		Loss of phosphorylation at T1057 (P = 0.0038);.;Loss of phosphorylation at T1057 (P = 0.0038);
MVP		0.50
MPC		0.25
ClinPred		0.17	T
GERP RS		5.4
Varity_R		0.050
gMVP		0.090

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: rs768663426; hg19: chr2-189912967;