rs773515722

Positions:

chr2-189052924-G-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP6BS2

The NM_000393.5(COL5A2):c.2648C>A(p.Ser883Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000434 in 1,613,918 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000047 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1O:1

Conservation

PhyloP100: 7.99

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A2. . Gene score misZ 2.4395 (greater than the threshold 3.09). Trascript score misZ 3.3523 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type.

BP6

Variant 2-189052924-G-T is Benign according to our data. Variant chr2-189052924-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213109.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2, not_provided=1}.

BS2

High AC in GnomAdExome4 at 68 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5 linkuse as main transcript	c.2648C>A	p.Ser883Tyr	missense_variant	39/54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 linkuse as main transcript	c.2510C>A	p.Ser837Tyr	missense_variant	42/57		XP_011508875.1
COL5A2	XM_047443251.1 linkuse as main transcript	c.2510C>A	p.Ser837Tyr	missense_variant	44/59		XP_047299207.1
COL5A2	XM_047443252.1 linkuse as main transcript	c.2510C>A	p.Ser837Tyr	missense_variant	43/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 linkuse as main transcript	c.2648C>A	p.Ser883Tyr	missense_variant	39/54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 linkuse as main transcript	c.1487C>A	p.Ser496Tyr	missense_variant	32/47	5		ENSP00000482184.1		A0A087WYX9

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251278

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135798

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000289

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:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000465

AC:

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000454

AC XY:

AN XY:

727204

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000594

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152104

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74282

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1Other:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 1

Benign:1Other:1

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 30, 2023	- -
not provided, no classification provided	phenotyping only	GenomeConnect - Invitae Patient Insights Network	-	Variant interpreted as Uncertain significance and reported on 03-17-2020 by Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information. -

Ehlers-Danlos syndrome, classic type, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 10, 2020

The COL5A2 c.2648C>A, p.Ser883Tyr variant (rs773515722), to our knowledge, has not been reported in the medical literature; however, this variant is listed in the ClinVar database (Variation ID: 213109). This variant is found in the general population with an overall allele frequency of 0.002% (4/251,278 alleles) in the Genome Aggregation Database. The serine at codon 883 is highly conserved, but computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.567). Based on the available information, the clinical significance of this variant is uncertain. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 06, 2018

TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. p.Ser883Tyr (S883Y) TCC>TAC: c.2648 C>A in exon 39 of the COL5A2 gene (NM_000393.3)A variant of unknown significance has been identified in the COL5A2 gene. The S883Y variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The S883Y variant was not observed in approximately 6500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The S883Y variant is a semi-conservative amino acid substitution, which may impact secondary protein structure as these residues differ in some properties. This substitution occurs at a position that is conserved in mammals. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, no missense mutations in nearby residues have been reported in association with a COL5A2-related disorder, suggesting this region of the protein may be tolerant of change. Also, the S883Y variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of missense mutations occur (Symoens et al., 2012).Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant. This variant was found in TAADV2-PANCARD. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.089

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Pathogenic

0.83

D;T;D

Eigen

Uncertain

0.63

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.95

.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Uncertain

0.56

D;D;D

MetaSVM

Uncertain

0.65

MutationAssessor

Benign

0.94

L;.;L

PrimateAI

Uncertain

0.68

PROVEAN

Uncertain

-2.8

D;.;.

REVEL

Uncertain

0.57

Sift

Uncertain

0.0050

D;.;.

Sift4G

Uncertain

0.037

D;D;.

Polyphen

0.99

D;.;D

Vest4

0.48

MutPred

0.30

Loss of glycosylation at S883 (P = 0.0161);.;Loss of glycosylation at S883 (P = 0.0161);

MVP

0.64

MPC

0.33

ClinPred

0.80

GERP RS

5.3

Varity_R

0.24

gMVP

0.35

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over