rs35852101

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000393.5(COL5A2):c.1535T>C(p.Val512Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0211 in 1,614,122 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.018 ( 25 hom., cov: 33)

Exomes 𝑓: 0.021 ( 416 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.18

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.011579573).

BP6

Variant 2-189066418-A-G is Benign according to our data. Variant chr2-189066418-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189066418-A-G is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0176 (2685/152316) while in subpopulation NFE AF= 0.0202 (1374/68028). AF 95% confidence interval is 0.0193. There are 25 homozygotes in gnomad4. There are 1308 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 2685 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.1535T>C	p.Val512Ala	missense_variant	Exon 23 of 54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.1397T>C	p.Val466Ala	missense_variant	Exon 26 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.1397T>C	p.Val466Ala	missense_variant	Exon 28 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.1397T>C	p.Val466Ala	missense_variant	Exon 27 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 link	c.1535T>C	p.Val512Ala	missense_variant	Exon 23 of 54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 link	c.374T>C	p.Val125Ala	missense_variant	Exon 16 of 47	5		ENSP00000482184.1		A0A087WYX9

Frequencies

GnomAD3 genomes

AF:

0.0177

AC:

2688

AN:

152198

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0109

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.0137

Gnomad ASJ

AF:

0.0242

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.0141

Gnomad FIN

AF:

0.0324

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0202

Gnomad OTH

AF:

0.0215

GnomAD3 exomes

AF:

0.0182

AC:

4570

AN:

251398

Hom.:

AF XY:

0.0185

AC XY:

2510

AN XY:

135870

show subpopulations

Gnomad AFR exome

AF:

0.0109

Gnomad AMR exome

AF:

0.0124

Gnomad ASJ exome

AF:

0.0277

Gnomad EAS exome

AF:

0.000326

Gnomad SAS exome

AF:

0.0125

Gnomad FIN exome

AF:

0.0325

Gnomad NFE exome

AF:

0.0216

Gnomad OTH exome

AF:

0.0218

GnomAD4 exome

AF:

0.0215

AC:

31380

AN:

1461806

Hom.:

416

Cov.:

AF XY:

0.0213

AC XY:

15461

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.00866

Gnomad4 AMR exome

AF:

0.0139

Gnomad4 ASJ exome

AF:

0.0292

Gnomad4 EAS exome

AF:

0.00385

Gnomad4 SAS exome

AF:

0.0136

Gnomad4 FIN exome

AF:

0.0299

Gnomad4 NFE exome

AF:

0.0229

Gnomad4 OTH exome

AF:

0.0200

GnomAD4 genome

AF:

0.0176

AC:

2685

AN:

152316

Hom.:

Cov.:

AF XY:

0.0176

AC XY:

1308

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0108

Gnomad4 AMR

AF:

0.0136

Gnomad4 ASJ

AF:

0.0242

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.0139

Gnomad4 FIN

AF:

0.0324

Gnomad4 NFE

AF:

0.0202

Gnomad4 OTH

AF:

0.0213

Alfa

AF:

0.0206

Hom.:

Bravo

AF:

0.0170

TwinsUK

AF:

0.0243

AC:

ALSPAC

AF:

0.0285

AC:

110

ESP6500AA

AF:

0.0116

AC:

ESP6500EA

AF:

0.0214

AC:

184

ExAC

AF:

0.0182

AC:

2213

Asia WGS

AF:

0.00318

AC:

AN:

3478

EpiCase

AF:

0.0224

EpiControl

AF:

0.0205

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 11, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Benign:3

Mar 21, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The COL5A2 c.1535T>C (p.Val512Ala) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant does not lie within a known functional domain (InterPro) and 2/4 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0182311 (2213/121386 control chromosomes [34 homozygotes]), which is approximately 14585 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

COL5A2: PP2, BS1, BS2 -

Ehlers-Danlos syndrome, classic type, 2

Benign:2

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Aug 07, 2015

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome type 7A

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome

Benign:1

Jul 16, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Benign

0.78

DEOGEN2

Benign

0.17

T;T;T

Eigen

Benign

-0.076

Eigen_PC

Benign

0.15

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

.;T;T

MetaRNN

Benign

0.012

T;T;T

MetaSVM

Uncertain

0.15

MutationAssessor

Benign

0.41

N;.;N

PrimateAI

Uncertain

0.59

PROVEAN

Benign

0.19

N;.;.

REVEL

Uncertain

0.44

Sift

Benign

1.0

T;.;.

Sift4G

Benign

1.0

T;T;.

Polyphen

0.46

P;.;P

Vest4

0.40

MPC

0.96

ClinPred

0.024

GERP RS

5.5

Varity_R

0.063

gMVP

0.43

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