2-189068038-G-A

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.033 ( 122 hom., cov: 32)

Exomes 𝑓: 0.047 ( 1839 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 5.43

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=0.0034188926).

BP6

Variant 2-189068038-G-A is Benign according to our data. Variant chr2-189068038-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189068038-G-A is described in Lovd as [Benign]. Variant chr2-189068038-G-A is described in Lovd as [Likely_benign].

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 link	c.1378C>T	p.Pro460Ser	missense_variant	Exon 21 of 54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.1240C>T	p.Pro414Ser	missense_variant	Exon 24 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.1240C>T	p.Pro414Ser	missense_variant	Exon 26 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	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 link	c.1378C>T	p.Pro460Ser	missense_variant	Exon 21 of 54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 link	c.359-1605C>T		intron_variant	Intron 15 of 46	5		ENSP00000482184.1		A0A087WYX9

Frequencies

GnomAD3 genomes

AF:

0.0328

AC:

4990

AN:

152096

Hom.:

122

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.0317

AC:

7951

AN:

251158

Hom.:

169

AF XY:

0.0322

AC XY:

4368

AN XY:

135726

show subpopulations

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 SAS exome

AF:

0.0196

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.:

AF XY:

0.0459

AC XY:

33363

AN XY:

727080

show subpopulations

Gnomad4 AFR exome

AF:

0.00708

Gnomad4 AMR exome

AF:

0.0166

Gnomad4 ASJ exome

AF:

0.0157

Gnomad4 EAS exome

AF:

0.000126

Gnomad4 SAS exome

AF:

0.0209

Gnomad4 FIN exome

AF:

0.0443

Gnomad4 NFE exome

AF:

0.0542

Gnomad4 OTH exome

AF:

0.0403

GnomAD4 genome

AF:

0.0328

AC:

4992

AN:

152214

Hom.:

122

Cov.:

AF XY:

0.0316

AC XY:

2351

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.00915

Gnomad4 AMR

AF:

0.0199

Gnomad4 ASJ

AF:

0.0130

Gnomad4 EAS

AF:

0.000580

Gnomad4 SAS

AF:

0.0174

Gnomad4 FIN

AF:

0.0497

Gnomad4 NFE

AF:

0.0517

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0430

Hom.:

261

Bravo

AF:

0.0282

TwinsUK

AF:

0.0647

AC:

240

ALSPAC

AF:

0.0558

AC:

215

ESP6500AA

AF:

0.0113

AC:

ESP6500EA

AF:

0.0543

AC:

467

ExAC

AF:

0.0324

AC:

3930

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0456

EpiControl

AF:

0.0441

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 2012	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Ehlers-Danlos syndrome, classic type, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 27, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2017	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. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 2015

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

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jun 10, 2022

- -

Ehlers-Danlos syndrome type 7A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.18

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

0.11

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

.;D

MetaRNN

Benign

0.0034

T;T

MetaSVM

Uncertain

0.055

MutationAssessor

Benign

1.7

L;L

PrimateAI

Benign

0.40

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

GERP RS

5.7

Varity_R

0.055

gMVP

0.053

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

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