rs10197596

Positions:

chr2-189039507-T-G

Variant summary

Our verdict is Benign. Variant got -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 (★★).

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:10

Conservation

PhyloP100: -1.99

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 -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 [Likely_benign]. Clinvar id is 136953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189039507-T-G is described in Lovd as [Benign].

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/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5 linkuse as main transcript	c.3690A>C	p.Thr1230Thr	synonymous_variant	51/54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 linkuse as main transcript	c.3552A>C	p.Thr1184Thr	synonymous_variant	54/57		XP_011508875.1
COL5A2	XM_047443251.1 linkuse as main transcript	c.3552A>C	p.Thr1184Thr	synonymous_variant	56/59		XP_047299207.1
COL5A2	XM_047443252.1 linkuse as main transcript	c.3552A>C	p.Thr1184Thr	synonymous_variant	55/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 linkuse as main transcript	c.3690A>C	p.Thr1230Thr	synonymous_variant	51/54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 linkuse as main transcript	c.2529A>C	p.Thr843Thr	synonymous_variant	44/47	5		ENSP00000482184.1		A0A087WYX9

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

GnomAD3 exomes

AF:

0.106

AC:

26624

AN:

250522

Hom.:

1594

AF XY:

0.111

AC XY:

15077

AN XY:

135500

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 SAS exome

AF:

0.158

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

Gnomad4 AFR exome

AF:

0.0732

Gnomad4 AMR exome

AF:

0.0714

Gnomad4 ASJ exome

AF:

0.168

Gnomad4 EAS exome

AF:

0.145

Gnomad4 SAS exome

AF:

0.160

Gnomad4 FIN exome

AF:

0.0931

Gnomad4 NFE exome

AF:

0.0983

Gnomad4 OTH exome

AF:

0.108

GnomAD4 genome

AF:

0.0962

AC:

14632

AN:

152120

Hom.:

739

Cov.:

AF XY:

0.0976

AC XY:

7262

AN XY:

74376

show subpopulations

Gnomad4 AFR

AF:

0.0723

Gnomad4 AMR

AF:

0.0989

Gnomad4 ASJ

AF:

0.173

Gnomad4 EAS

AF:

0.119

Gnomad4 SAS

AF:

0.151

Gnomad4 FIN

AF:

0.0892

Gnomad4 NFE

AF:

0.102

Gnomad4 OTH

AF:

0.105

Alfa

AF:

0.107

Hom.:

1256

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:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 31, 2017	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 05, 2012	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. -

Ehlers-Danlos syndrome, classic type, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 17, 2017	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. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 18, 2015

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

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.56

CADD

Benign

0.89

DANN

Benign

0.70

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

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