rs117917418

Variant summary

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

The NM_000393.5(COL5A2):c.98-12T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,606,384 control chromosomes in the GnomAD database, including 717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.013 ( 61 hom., cov: 32)

Exomes 𝑓: 0.011 ( 656 hom. )

Consequence

COL5A2
NM_000393.5 splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.0002545

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.681

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 2-189110461-A-C is Benign according to our data. Variant chr2-189110461-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 136960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189110461-A-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0682 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE
COL5A2	NM_000393.5 linkuse as main transcript	c.98-12T>G	splice_polypyrimidine_tract_variant, intron_variant	ENST00000374866.9
COL5A2	XM_011510573.4 linkuse as main transcript	c.-41-12T>G	splice_polypyrimidine_tract_variant, intron_variant
COL5A2	XM_047443251.1 linkuse as main transcript	c.-41-12T>G	splice_polypyrimidine_tract_variant, intron_variant
COL5A2	XM_047443252.1 linkuse as main transcript	c.-41-12T>G	splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	Effect	TSL	MANE	Appris
COL5A2	ENST00000374866.9 linkuse as main transcript	c.98-12T>G	splice_polypyrimidine_tract_variant, intron_variant	1	NM_000393.5	P1
COL5A2	ENST00000618828.1 linkuse as main transcript	c.-533-12T>G	splice_polypyrimidine_tract_variant, intron_variant	5
COL5A2	ENST00000649966.1 linkuse as main transcript	c.-41-12T>G	splice_polypyrimidine_tract_variant, intron_variant

Frequencies

GnomAD3 genomes

AF:

0.0129

AC:

1960

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00347

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0716

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.0354

Gnomad SAS

AF:

0.00726

Gnomad FIN

AF:

0.000847

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00660

Gnomad OTH

AF:

0.0191

GnomAD3 exomes

AF:

0.0284

AC:

7086

AN:

249584

Hom.:

486

AF XY:

0.0233

AC XY:

3144

AN XY:

135142

show subpopulations

Gnomad AFR exome

AF:

0.00289

Gnomad AMR exome

AF:

0.153

Gnomad ASJ exome

AF:

0.000896

Gnomad EAS exome

AF:

0.0304

Gnomad SAS exome

AF:

0.00742

Gnomad FIN exome

AF:

0.00111

Gnomad NFE exome

AF:

0.00726

Gnomad OTH exome

AF:

0.0234

GnomAD4 exome

AF:

0.0113

AC:

16360

AN:

1454072

Hom.:

656

Cov.:

AF XY:

0.0106

AC XY:

7666

AN XY:

724086

show subpopulations

Gnomad4 AFR exome

AF:

0.00201

Gnomad4 AMR exome

AF:

0.144

Gnomad4 ASJ exome

AF:

0.000882

Gnomad4 EAS exome

AF:

0.0619

Gnomad4 SAS exome

AF:

0.00723

Gnomad4 FIN exome

AF:

0.00137

Gnomad4 NFE exome

AF:

0.00542

Gnomad4 OTH exome

AF:

0.00981

GnomAD4 genome

AF:

0.0129

AC:

1963

AN:

152312

Hom.:

Cov.:

AF XY:

0.0137

AC XY:

1017

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.00346

Gnomad4 AMR

AF:

0.0717

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.0355

Gnomad4 SAS

AF:

0.00726

Gnomad4 FIN

AF:

0.000847

Gnomad4 NFE

AF:

0.00660

Gnomad4 OTH

AF:

0.0189

Alfa

AF:

0.0105

Hom.:

Bravo

AF:

0.0198

Asia WGS

AF:

0.0160

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 28, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2013	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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 09, 2017

This alteration is classified as likely 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, classic type, 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

Cadd

Benign

Dann

Benign

0.85

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00025

dbscSNV1_RF

Benign

0.092

SpliceAI score (max)

0.030

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