rs10208525

Positions:

• chr2-189039477-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000393.5(COL5A2):​c.3720T>C​(p.Tyr1240=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,900 control chromosomes in the GnomAD database, including 9,098 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 (724 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8374 hom.)
• Consequence: COL5A2 NM_000393.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.574

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-189039477-A-G is Benign according to our data. Variant chr2-189039477-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 136954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189039477-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.574 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	UniProt
COL5A2	NM_000393.5	c.3720T>C	p.Tyr1240=	synonymous_variant	51/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.3582T>C	p.Tyr1194=	synonymous_variant	54/57
COL5A2	XM_047443251.1	c.3582T>C	p.Tyr1194=	synonymous_variant	56/59
COL5A2	XM_047443252.1	c.3582T>C	p.Tyr1194=	synonymous_variant	55/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.3720T>C	p.Tyr1240=	synonymous_variant	51/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.2559T>C	p.Tyr853=	synonymous_variant	44/47	5

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14542 AN: 152028 Hom.: 724 Cov.: 32

Gnomad AFR AF: 0.0721

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0989

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0890

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.105

GnomAD3 exomes AF: 0.105 AC: 26350 AN: 251060 Hom.: 1559 AF XY: 0.110 AC XY: 14926 AN XY: 135712

Gnomad AFR exome AF: 0.0718

Gnomad AMR exome AF: 0.0658

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.105

Gnomad SAS exome AF: 0.157

Gnomad FIN exome AF: 0.0903

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.103 AC: 150569 AN: 1461754 Hom.: 8374 Cov.: 32 AF XY: 0.106 AC XY: 76882 AN XY: 727178

Gnomad4 AFR exome AF: 0.0732

Gnomad4 AMR exome AF: 0.0714

Gnomad4 ASJ exome AF: 0.167

Gnomad4 EAS exome AF: 0.121

Gnomad4 SAS exome AF: 0.160

Gnomad4 FIN exome AF: 0.0930

Gnomad4 NFE exome AF: 0.0985

Gnomad4 OTH exome AF: 0.108

GnomAD4 genome AF: 0.0956 AC: 14546 AN: 152146 Hom.: 724 Cov.: 32 AF XY: 0.0969 AC XY: 7208 AN XY: 74376

Gnomad4 AFR AF: 0.0723

Gnomad4 AMR AF: 0.0988

Gnomad4 ASJ AF: 0.172

Gnomad4 EAS AF: 0.103

Gnomad4 SAS AF: 0.151

Gnomad4 FIN AF: 0.0890

Gnomad4 NFE AF: 0.102

Gnomad4 OTH AF: 0.105

Alfa AF: 0.107 Hom.: 1256

Bravo AF: 0.0938

Asia WGS AF: 0.123 AC: 426 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.117

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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. -
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	-	- -

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 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. -

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

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 15, 2017

Variant summary: The c.3720T>C (p.Tyr1240=) in COL5A2 gene is a synonymous change that involves a non-conserved nucleotide. 5/5 programs in Alamut predict that this variant does not affect the normal splicing pattern, 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 0.1061 (12774/120436 chrs tested), including numerous homozygous occurrences. This frequency exceeds the estimated maximum allele frequency for a pathogenic allele in this gene (0.000006). The variant of interest has been cited 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. -

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	-0.60
CADD	Benign	0.055
DANN	Benign	0.19

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

Other links and lift over

dbSNP: rs10208525; hg19: chr2-189904203; COSMIC: COSV66408953;