rs78905646

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000393.5(COL5A2):c.4449C>T(p.Gly1483Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0212 in 1,613,862 control chromosomes in the GnomAD database, including 441 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. G1483G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.016 ( 26 hom., cov: 32)

Exomes 𝑓: 0.022 ( 415 hom. )

Consequence

COL5A2
NM_000393.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.632

Publications

5 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 -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP6

Variant 2-189034121-G-A is Benign according to our data. Variant chr2-189034121-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.632 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0158 (2403/152166) while in subpopulation NFE AF = 0.0207 (1408/67990). AF 95% confidence interval is 0.0198. There are 26 homozygotes in GnomAd4. There are 1190 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2403 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.4449C>T	p.Gly1483Gly	synonymous_variant	Exon 54 of 54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.4311C>T	p.Gly1437Gly	synonymous_variant	Exon 57 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.4311C>T	p.Gly1437Gly	synonymous_variant	Exon 59 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.4311C>T	p.Gly1437Gly	synonymous_variant	Exon 58 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 link	c.4449C>T	p.Gly1483Gly	synonymous_variant	Exon 54 of 54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 link	c.3288C>T	p.Gly1096Gly	synonymous_variant	Exon 47 of 47	5		ENSP00000482184.1		A0A087WYX9

Frequencies

GnomAD3 genomes

AF:

0.0158

AC:

2404

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00382

Gnomad AMI

AF:

0.105

Gnomad AMR

AF:

0.0123

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.00347

Gnomad SAS

AF:

0.0147

Gnomad FIN

AF:

0.0324

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.0207

Gnomad OTH

AF:

0.0182

GnomAD2 exomes

AF:

0.0175

AC:

4398

AN:

251166

AF XY:

0.0181

show subpopulations

Gnomad AFR exome

AF:

0.00388

Gnomad AMR exome

AF:

0.0105

Gnomad ASJ exome

AF:

0.0266

Gnomad EAS exome

AF:

0.000599

Gnomad FIN exome

AF:

0.0326

Gnomad NFE exome

AF:

0.0218

Gnomad OTH exome

AF:

0.0173

GnomAD4 exome

AF:

0.0217

AC:

31755

AN:

1461696

Hom.:

415

Cov.:

AF XY:

0.0216

AC XY:

15683

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.00332

AC:

111

AN:

33470

American (AMR)

AF:

0.0116

AC:

519

AN:

44690

Ashkenazi Jewish (ASJ)

AF:

0.0279

AC:

730

AN:

26124

East Asian (EAS)

AF:

0.00574

AC:

228

AN:

39698

South Asian (SAS)

AF:

0.0143

AC:

1232

AN:

86254

European-Finnish (FIN)

AF:

0.0299

AC:

1599

AN:

53396

Middle Eastern (MID)

AF:

0.0106

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0235

AC:

26093

AN:

1111912

Other (OTH)

AF:

0.0196

AC:

1182

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

1764

3528

5291

7055

8819

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

978

1956

2934

3912

4890

<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:

0.0158

AC:

2403

AN:

152166

Hom.:

Cov.:

AF XY:

0.0160

AC XY:

1190

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.00385

AC:

160

AN:

41532

American (AMR)

AF:

0.0122

AC:

186

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

AN:

3468

East Asian (EAS)

AF:

0.00348

AC:

AN:

5176

South Asian (SAS)

AF:

0.0145

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0324

AC:

343

AN:

10590

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0207

AC:

1408

AN:

67990

Other (OTH)

AF:

0.0180

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

127

253

380

506

633

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<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:

0.0188

Hom.:

Bravo

AF:

0.0145

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0226

EpiControl

AF:

0.0208

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

Jul 21, 2023

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

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. -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

BS1;BP7 -

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

Mar 03, 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

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 type 7A

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

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

-0.41

CADD

Benign

9.4

(source)

DANN

Benign

0.61

PhyloP100

0.63

Mutation Taster

=100/0

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