rs145850743

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2

The NM_000393.5(COL5A2):c.1301C>T(p.Thr434Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,660 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. T434K) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 21 hom. )

Consequence

COL5A2
NM_000393.5 missense, splice_region

Scores

Splicing: ADA: 0.002463

Clinical Significance

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

Conservation

PhyloP100: 2.47

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 -15 ACMG points.

PP2

Missense variant where missense usually causes diseases, COL5A2

BP4

Computational evidence support a benign effect (MetaRNN=0.01739955).

BP6

Variant 2-189068227-G-A is Benign according to our data. Variant chr2-189068227-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 212979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189068227-G-A is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd at 181 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A2	NM_000393.5 linkuse as main transcript	c.1301C>T	p.Thr434Met	missense_variant, splice_region_variant	20/54	ENST00000374866.9
COL5A2	XM_011510573.4 linkuse as main transcript	c.1163C>T	p.Thr388Met	missense_variant, splice_region_variant	23/57
COL5A2	XM_047443251.1 linkuse as main transcript	c.1163C>T	p.Thr388Met	missense_variant, splice_region_variant	25/59
COL5A2	XM_047443252.1 linkuse as main transcript	c.1163C>T	p.Thr388Met	missense_variant, splice_region_variant	24/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9 linkuse as main transcript	c.1301C>T	p.Thr434Met	missense_variant, splice_region_variant	20/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1 linkuse as main transcript	c.359-1794C>T		intron_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00188

AC:

472

AN:

251210

Hom.:

AF XY:

0.00199

AC XY:

270

AN XY:

135748

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.0273

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00163

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00116

AC:

1692

AN:

1461376

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

895

AN XY:

727028

show subpopulations

Gnomad4 AFR exome

AF:

0.000239

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0293

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00173

Gnomad4 FIN exome

AF:

0.000374

Gnomad4 NFE exome

AF:

0.000512

Gnomad4 OTH exome

AF:

0.00263

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152284

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000217

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.0268

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.000188

Gnomad4 NFE

AF:

0.000676

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.00202

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00180

AC:

219

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00154

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:6

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jul 11, 2017	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2019	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2024	COL5A2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 31, 2017	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 21, 2023

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 15, 2017

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

Sep 28, 2021

- -

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, 2

Benign:1

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. -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

Cadd

Benign

Dann

Uncertain

0.99

DEOGEN2

Benign

0.35

T;T

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.95

M_CAP

Benign

0.059

MetaRNN

Benign

0.017

T;T

MetaSVM

Uncertain

-0.073

MutationAssessor

Benign

1.0

L;L

MutationTaster

Benign

0.98

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

N;.

REVEL

Benign

0.23

Sift

Benign

0.088

T;.

Sift4G

Benign

0.14

T;.

Polyphen

0.025

B;B

Vest4

0.31

MVP

0.65

MPC

0.94

ClinPred

0.038

GERP RS

4.3

Varity_R

0.035

gMVP

0.099

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.20

SpliceAI score (max)

0.010

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