rs148220961

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000393.5(COL5A2):c.370-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,609,678 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0073 ( 8 hom., cov: 33)

Exomes 𝑓: 0.0075 ( 70 hom. )

Consequence

COL5A2
NM_000393.5 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.299

Publications

3 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.71).

BP6

Variant 2-189098775-G-A is Benign according to our data. Variant chr2-189098775-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0073 (1112/152254) while in subpopulation AMR AF = 0.0172 (263/15286). AF 95% confidence interval is 0.0155. There are 8 homozygotes in GnomAd4. There are 523 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 1112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.370-16C>T	intron_variant	Intron 4 of 53	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.232-16C>T	intron_variant	Intron 7 of 56		XP_011508875.1
COL5A2	XM_047443251.1 link	c.232-16C>T	intron_variant	Intron 9 of 58		XP_047299207.1
COL5A2	XM_047443252.1 link	c.232-16C>T	intron_variant	Intron 8 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL5A2	ENST00000374866.9 link	c.370-16C>T	intron_variant	Intron 4 of 53	1	NM_000393.5	ENSP00000364000.3	P05997
COL5A2	ENST00000618828.1 link	c.-261-16C>T	intron_variant	Intron 4 of 46	5		ENSP00000482184.1	A0A087WYX9
COL5A2	ENST00000649966.1 link	c.232-16C>T	intron_variant	Intron 4 of 10			ENSP00000496785.1	A0A3B3IRH9

Frequencies

GnomAD3 genomes

AF:

0.00732

AC:

1114

AN:

152136

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.0362

Gnomad AMR

AF:

0.0172

Gnomad ASJ

AF:

0.0395

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000827

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.00838

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.00737

AC:

1848

AN:

250852

AF XY:

0.00719

show subpopulations

Gnomad AFR exome

AF:

0.00148

Gnomad AMR exome

AF:

0.0113

Gnomad ASJ exome

AF:

0.0346

Gnomad EAS exome

AF:

0.0000546

Gnomad FIN exome

AF:

0.000652

Gnomad NFE exome

AF:

0.00839

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.00755

AC:

11003

AN:

1457424

Hom.:

Cov.:

AF XY:

0.00739

AC XY:

5363

AN XY:

725314

show subpopulations

African (AFR)

AF:

0.00147

AC:

AN:

33386

American (AMR)

AF:

0.0124

AC:

552

AN:

44676

Ashkenazi Jewish (ASJ)

AF:

0.0342

AC:

892

AN:

26060

East Asian (EAS)

AF:

0.0000253

AC:

AN:

39600

South Asian (SAS)

AF:

0.00123

AC:

106

AN:

86142

European-Finnish (FIN)

AF:

0.000677

AC:

AN:

53140

Middle Eastern (MID)

AF:

0.0158

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.00792

AC:

8777

AN:

1108436

Other (OTH)

AF:

0.00829

AC:

499

AN:

60226

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

477

955

1432

1910

2387

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.00730

AC:

1112

AN:

152254

Hom.:

Cov.:

AF XY:

0.00702

AC XY:

523

AN XY:

74452

show subpopulations

African (AFR)

AF:

0.00185

AC:

AN:

41542

American (AMR)

AF:

0.0172

AC:

263

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0395

AC:

137

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.000621

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00838

AC:

570

AN:

68006

Other (OTH)

AF:

0.0104

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

104

156

208

260

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00980

Hom.:

Bravo

AF:

0.00826

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Nov 29, 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

- -

not provided

Benign:2

Mar 16, 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.370-16C>T variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing while ESE finder predicts the loss of a SRp40 binding motif. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 762/119346 control chromosomes (2 homozygotes) at a frequency of 0.0063848, which is approximately 1022 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor 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

- -

Ehlers-Danlos syndrome, classic type, 2

Benign:1

Oct 28, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, classic type

Benign:1

Nov 01, 2016

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Feb 02, 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

-0.71

CADD

Benign

3.7

(source)

DANN

Benign

0.78

PhyloP100

-0.30

Mutation Taster

=100/0

polymorphism

(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