rs372220538

chr2-189050570-G-A

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2 BP4_Moderate BS2

The NM_000393.5(COL5A2):c.3038C>T(p.Ala1013Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000549 in 1,549,480 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. A1013A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000057 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense, splice_region
• Scores: Splicing: ADA: 0.5342
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:5
• Conservation: PhyloP100: 4.02

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 -5 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.24092868).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.3038C>T	p.Ala1013Val	missense_variant, splice_region_variant	43/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.2900C>T	p.Ala967Val	missense_variant, splice_region_variant	46/57
COL5A2	XM_047443251.1	c.2900C>T	p.Ala967Val	missense_variant, splice_region_variant	48/59
COL5A2	XM_047443252.1	c.2900C>T	p.Ala967Val	missense_variant, splice_region_variant	47/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.3038C>T	p.Ala1013Val	missense_variant, splice_region_variant	43/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.1877C>T	p.Ala626Val	missense_variant, splice_region_variant	36/47	5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152126 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000320 AC: 5 AN: 156464 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 82340

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000404

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000265

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000165

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000565 AC: 79 AN: 1397354 Hom.: 0 Cov.: 30 AF XY: 0.0000435 AC XY: 30 AN XY: 689388

Gnomad4 AFR exome AF: 0.000158

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000140

Gnomad4 SAS exome AF: 0.0000505

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000585

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152126 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74304

Gnomad4 AFR AF: 0.0000966

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000564 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000479 AC: 2

ESP6500EA AF: 0.000124 AC: 1

ExAC AF: 0.0000368 AC: 3

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 09, 2022	Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2023	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 13, 2017	One variant of uncertain clinical significance, c.3038C>T; p.Ala1013Val, was detected in the COL5A2 gene by massively parallel sequencing and confirmed by Sanger sequencing. The p.Ala1013Val (rs372220538) is listed in the Exome Aggregation Consortium Browser with an overall allele frequency of 0.01 percent (identified in 2 out of 20,648 chromosomes) and with frequency of 0.07 percent (identified in 2 out of 2726 chromosomes) in African populations. This variant has not been previously reported in the scientific literature or gene-specific variant databases. We have previously identified this variant in an individual with subtle skeletal findings who also carried pathogenic variant in the SMAD3 gene. The alanine 1013 is highly conserved up to Xenopus tropicalis but computational prediction programs do not agree in assessing the effect of this variant (SIFT: tolerated, PolyPhen-2: benign, and MutationTaster: disease causing). p.Ala1013Val is not located in the triple helix domain and computational splice prediction programs do not suggest significant effect on splicing (Alamut software v.2.7.1).. Altogether, there is not enough information to classify this variant with certainty. Pathogenic COL5A2 variants are associated with Ehlers-Danlos syndrome, type I (MIM:130000). -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 11, 2020

The p.A1013V variant (also known as c.3038C>T), located in coding exon 43 of the COL5A2 gene, results from a C to T substitution at nucleotide position 3038. The alanine at codon 1013 is replaced by valine, an amino acid with similar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 1013 of the COL5A2 protein (p.Ala1013Val). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 576774). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C55"). 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	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;T
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.24	T;T;T
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.5	L;.;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.4	N;.;.
REVEL	Uncertain	0.33
Sift	Benign	0.47	T;.;.
Sift4G	Benign	0.27	T;T;.
Polyphen		0.92	P;.;P
Vest4		0.33
MVP		0.72
MPC		0.26
ClinPred		0.096	T
GERP RS		5.1
Varity_R		0.028
gMVP		0.29

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.53
dbscSNV1_RF	Benign	0.46
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: rs372220538; hg19: chr2-189915296;