rs146175905

chr2-189058862-G-Achr2-189058862-G-C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000393.5(COL5A2):c.2117C>T(p.Pro706Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000484 in 1,613,068 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. P706P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.18

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 -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.109802485).
• BP6: Variant 2-189058862-G-A is Benign according to our data. Variant chr2-189058862-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 459732.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.2117C>T	p.Pro706Leu	missense_variant	32/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.1979C>T	p.Pro660Leu	missense_variant	35/57
COL5A2	XM_047443251.1	c.1979C>T	p.Pro660Leu	missense_variant	37/59
COL5A2	XM_047443252.1	c.1979C>T	p.Pro660Leu	missense_variant	36/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.2117C>T	p.Pro706Leu	missense_variant	32/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.956C>T	p.Pro319Leu	missense_variant	25/47	5
COL5A2	ENST00000470524.2	n.223C>T		non_coding_transcript_exon_variant	5/8	5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 151440 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000388

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000198

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.000481

GnomAD3 exomes AF: 0.000103 AC: 26 AN: 251230 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135816

Gnomad AFR exome AF: 0.000739

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000131

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000369 AC: 54 AN: 1461522 Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27 AN XY: 727072

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.0000895

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000108

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000158 AC: 24 AN: 151546 Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15 AN XY: 74044

Gnomad4 AFR AF: 0.000387

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.000476

Alfa AF: 0.0000965 Hom.: 0

Bravo AF: 0.000242

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000115 AC: 14

EpiCase AF: 0.0000546

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The COL5A2 p.Pro706Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs146175905) and in ClinVar (classified as a VUS by Invitae and Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital). The variant was also identified in control databases in 28 of 282454 chromosomes at a frequency of 0.000099 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 14 of 24910 chromosomes (freq: 0.000562), Other in 1 of 7210 chromosomes (freq: 0.000139), South Asian in 4 of 30594 chromosomes (freq: 0.000131), Latino in 4 of 35382 chromosomes (freq: 0.000113) and European (non-Finnish) in 5 of 129032 chromosomes (freq: 0.000039); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Pro706 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Feb 15, 2022	Has been reported in an individual with congenital heart defects, who also harbored variants in several other genes (Jin et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28166811, 28991257, 27535533) -

Marfan syndrome Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital

Dec 30, 2016

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2019

The p.P706L variant (also known as c.2117C>T), located in coding exon 32 of the COL5A2 gene, results from a C to T substitution at nucleotide position 2117. The proline at codon 706 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with unspecified conotruncal defects who also carried the COL5A2 p.R1070H alteration (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601). This amino acid position is highly 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 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 26, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.091	T
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	25
Dann	Uncertain	0.97
DEOGEN2	Benign	0.39	T;T;T
Eigen	Benign	0.12
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Pathogenic	0.85	D
MutationAssessor	Benign	0.65	N;.;N
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-3.5	D;.;.
REVEL	Uncertain	0.48
Sift	Benign	0.38	T;.;.
Sift4G	Benign	0.18	T;T;.
Polyphen		0.64	P;.;P
Vest4		0.59
MVP		0.60
MPC		0.26
ClinPred		0.045	T
GERP RS		5.6
Varity_R		0.20
gMVP		0.24

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: rs146175905; hg19: chr2-189923588;