2-189039507-T-G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000393.5(COL5A2):c.3690A>C(p.Thr1230Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,802 control chromosomes in the GnomAD database, including 9,249 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1230T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.096 ( 739 hom., cov: 31)

Exomes 𝑓: 0.10 ( 8510 hom. )

Consequence

COL5A2
NM_000393.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -1.99

Publications

13 publications found

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 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

COL5A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.56).

BP6

Variant 2-189039507-T-G is Benign according to our data. Variant chr2-189039507-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.99 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
COL5A2	NM_000393.5 link	c.3690A>C	p.Thr1230Thr	synonymous_variant	Exon 51 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4 link	c.3552A>C	p.Thr1184Thr	synonymous_variant	Exon 54 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.3552A>C	p.Thr1184Thr	synonymous_variant	Exon 56 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.3552A>C	p.Thr1184Thr	synonymous_variant	Exon 55 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 link	c.3690A>C	p.Thr1230Thr	synonymous_variant	Exon 51 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1 link	c.2529A>C	p.Thr843Thr	synonymous_variant	Exon 44 of 47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes

AF:

0.0962

AC:

14627

AN:

152002

Hom.:

739

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0721

Gnomad AMI

AF:

0.0625

Gnomad AMR

AF:

0.0990

Gnomad ASJ

AF:

0.173

Gnomad EAS

AF:

0.119

Gnomad SAS

AF:

0.151

Gnomad FIN

AF:

0.0892

Gnomad MID

AF:

0.146

Gnomad NFE

AF:

0.102

Gnomad OTH

AF:

0.105

GnomAD2 exomes

AF:

0.106

AC:

26624

AN:

250522

AF XY:

0.111

show subpopulations

Gnomad AFR exome

AF:

0.0719

Gnomad AMR exome

AF:

0.0659

Gnomad ASJ exome

AF:

0.169

Gnomad EAS exome

AF:

0.123

Gnomad FIN exome

AF:

0.0900

Gnomad NFE exome

AF:

0.104

Gnomad OTH exome

AF:

0.117

GnomAD4 exome

AF:

0.104

AC:

151413

AN:

1461682

Hom.:

8510

Cov.:

AF XY:

0.106

AC XY:

77299

AN XY:

727144

show subpopulations

African (AFR)

AF:

0.0732

AC:

2451

AN:

33478

American (AMR)

AF:

0.0714

AC:

3194

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.168

AC:

4383

AN:

26132

East Asian (EAS)

AF:

0.145

AC:

5767

AN:

39692

South Asian (SAS)

AF:

0.160

AC:

13817

AN:

86238

European-Finnish (FIN)

AF:

0.0931

AC:

4970

AN:

53386

Middle Eastern (MID)

AF:

0.172

AC:

986

AN:

5728

European-Non Finnish (NFE)

AF:

0.0983

AC:

109311

AN:

1111922

Other (OTH)

AF:

0.108

AC:

6534

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

8056

16112

24168

32224

40280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

3998

7996

11994

15992

19990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0962

AC:

14632

AN:

152120

Hom.:

739

Cov.:

AF XY:

0.0976

AC XY:

7262

AN XY:

74376

show subpopulations

African (AFR)

AF:

0.0723

AC:

3003

AN:

41522

American (AMR)

AF:

0.0989

AC:

1512

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.173

AC:

599

AN:

3466

East Asian (EAS)

AF:

0.119

AC:

615

AN:

5156

South Asian (SAS)

AF:

0.151

AC:

726

AN:

4812

European-Finnish (FIN)

AF:

0.0892

AC:

944

AN:

10588

Middle Eastern (MID)

AF:

0.139

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.102

AC:

6913

AN:

67968

Other (OTH)

AF:

0.105

AC:

222

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

677

1354

2032

2709

3386

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

172

344

516

688

860

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.105

Hom.:

1500

Bravo

AF:

0.0944

Asia WGS

AF:

0.126

AC:

437

AN:

3478

EpiCase

AF:

0.115

EpiControl

AF:

0.117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

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

Nov 05, 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.

Mar 31, 2017

Eurofins Ntd Llc (ga)

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 26, 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 17, 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 c.3690A>C (p.Thr1230=) in COL5A2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant eliminates a cryptic acceptor cite, however no functional studies supporting these predictions were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.1081 (12897/119348 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.0000063). The variant of interest hasbeen reported as Benign by multiple reputable databases/clinical laboratories. Taking together, based on the prevalence of this variant in general population the variant was 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 18, 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, 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

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.89

(source)

DANN

Benign

0.70

PhyloP100

-2.0

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over