rs56310996

Positions:

• chr2-189083970-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000393.5(COL5A2):​c.852+14C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.143 in 1,594,382 control chromosomes in the GnomAD database, including 17,145 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1524 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15621 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.101

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-189083970-G-A is Benign according to our data. Variant chr2-189083970-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189083970-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.852+14C>T		intron_variant		ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.714+14C>T		intron_variant			XP_011508875.1
COL5A2	XM_047443251.1	c.714+14C>T		intron_variant			XP_047299207.1
COL5A2	XM_047443252.1	c.714+14C>T		intron_variant			XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.852+14C>T		intron_variant		1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.222+14C>T		intron_variant		5		ENSP00000482184

Frequencies

GnomAD3 genomes AF: 0.142 AC: 21603 AN: 151976 Hom.: 1527 Cov.: 32

Gnomad AFR AF: 0.131

Gnomad AMI AF: 0.172

Gnomad AMR AF: 0.136

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0984

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.159

GnomAD3 exomes AF: 0.143 AC: 35962 AN: 251038 Hom.: 2801 AF XY: 0.148 AC XY: 20145 AN XY: 135674

Gnomad AFR exome AF: 0.128

Gnomad AMR exome AF: 0.0971

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.0973

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.148

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.143 AC: 206569 AN: 1442290 Hom.: 15621 Cov.: 28 AF XY: 0.146 AC XY: 104683 AN XY: 718798

Gnomad4 AFR exome AF: 0.123

Gnomad4 AMR exome AF: 0.104

Gnomad4 ASJ exome AF: 0.225

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.141

Gnomad4 NFE exome AF: 0.140

Gnomad4 OTH exome AF: 0.150

GnomAD4 genome AF: 0.142 AC: 21610 AN: 152092 Hom.: 1524 Cov.: 32 AF XY: 0.143 AC XY: 10639 AN XY: 74334

Gnomad4 AFR AF: 0.131

Gnomad4 AMR AF: 0.136

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.0978

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.138

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.158

Alfa AF: 0.153 Hom.: 357

Bravo AF: 0.140

Asia WGS AF: 0.140 AC: 486 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 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	PreventionGenetics, part of Exact Sciences	-	- -

Ehlers-Danlos syndrome, classic type, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
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. -

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 15, 2017	Variant summary: c.852+14C>T in COL5A2 gene is an intronic change that involves a non-conserved nucleotide. 4/5 programs in Alamut predict that this variant does not affect a normal splicing pattern, however no functional studies supporting this notion were published at the time of evaluation. The variant is present in the control population dataset of ExAC at frequency of 0.1446 (17522 /121190 chrs tested) including numerous homozygous occurrences. The observed frequencies exceed the maximum expected allele frequency for a pathogenic variant of 0.0000063 suggesting that it is a benign polymorphism. The variant of interest has been cited as Benign/Likely Benign by multiple reputable databases/clinical laboratory. Taking together, based on the prevalence of this variant in general population the variant was classified as Benign. -

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	-0.89
CADD	Benign	3.7
DANN	Benign	0.27

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: rs56310996; hg19: chr2-189948696; COSMIC: COSV66410269;