rs35830636

Variant names:

• chr2-189068038-G-A
• rs35830636
• NM_000393.5:c.1378C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000393.5(COL5A2):​c.1378C>T​(p.Pro460Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0454 in 1,613,706 control chromosomes in the GnomAD database, including 1,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P460L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.033 (122 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1839 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 5.43
• Publications: 19 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034188926).
• BP6: Variant 2-189068038-G-A is Benign according to our data. Variant chr2-189068038-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1378C>T	p.Pro460Ser	missense_variant	Exon 21 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1240C>T	p.Pro414Ser	missense_variant	Exon 24 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.1240C>T	p.Pro414Ser	missense_variant	Exon 26 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.1240C>T	p.Pro414Ser	missense_variant	Exon 25 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1378C>T	p.Pro460Ser	missense_variant	Exon 21 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.359-1605C>T		intron_variant	Intron 15 of 46	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4990 AN: 152096 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0517

Gnomad OTH AF: 0.0211

GnomAD2 exomes AF: 0.0317 AC: 7951 AN: 251158 AF XY: 0.0322

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0467 AC: 68255 AN: 1461492 Hom.: 1839 Cov.: 32 AF XY: 0.0459 AC XY: 33363 AN XY: 727080

African (AFR) AF: 0.00708 AC: 237 AN: 33472

American (AMR) AF: 0.0166 AC: 743 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.0157 AC: 409 AN: 26134

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39698

South Asian (SAS) AF: 0.0209 AC: 1799 AN: 86254

European-Finnish (FIN) AF: 0.0443 AC: 2364 AN: 53414

Middle Eastern (MID) AF: 0.00659 AC: 38 AN: 5764

European-Non Finnish (NFE) AF: 0.0542 AC: 60226 AN: 1111676

Other (OTH) AF: 0.0403 AC: 2434 AN: 60382

GnomAD4 genome AF: 0.0328 AC: 4992 AN: 152214 Hom.: 122 Cov.: 32 AF XY: 0.0316 AC XY: 2351 AN XY: 74398

African (AFR) AF: 0.00915 AC: 380 AN: 41544

American (AMR) AF: 0.0199 AC: 304 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.0174 AC: 84 AN: 4818

European-Finnish (FIN) AF: 0.0497 AC: 526 AN: 10594

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0517 AC: 3516 AN: 68016

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0429 Hom.: 547

Bravo AF: 0.0282

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0558 AC: 215

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.0543 AC: 467

ExAC AF: 0.0324 AC: 3930

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0456

EpiControl AF: 0.0441

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

-

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Nov 27, 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

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 2 Benign:2

Jan 12, 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. -

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

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.1378C>T (p.Pro460Ser) 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 UniProt) and 2/3 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 0.0324101 (3927/121166 control chromosomes [80 homozygotes]), which is approximately 25928 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

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Feb 04, 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 Benign:1

Jun 10, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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, 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	0.065
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
MetaRNN	Benign	0.0034	T;T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.7	L;L
PhyloP100		5.4
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.98	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.13	T;.
Sift4G	Benign	0.29	T;.
Polyphen		0.019	B;B
Vest4		0.12
MPC		0.75
ClinPred		0.018	T
GERP RS		5.7
Varity_R		0.055
gMVP		0.053
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs35830636; hg19: chr2-189932764; COSMIC: COSV108216386; COSMIC: COSV108216386;