2-189088782-C-T

Position:

• chr2-189088782-C-T

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.568-10G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.142 in 1,608,852 control chromosomes in the GnomAD database, including 17,238 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1373 hom., cov: 33)
  • Exomes 𝑓: 0.14 (15865 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Scores: Splicing: ADA: 0.001508
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.99

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=-0.61).
• BP6: Variant 2-189088782-C-T is Benign according to our data. Variant chr2-189088782-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189088782-C-T 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.568-10G>A		intron_variant		ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.430-10G>A		intron_variant			XP_011508875.1
COL5A2	XM_047443251.1	c.430-10G>A		intron_variant			XP_047299207.1
COL5A2	XM_047443252.1	c.430-10G>A		intron_variant			XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.568-10G>A		intron_variant		1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.-63-10G>A		intron_variant		5		ENSP00000482184.1
COL5A2	ENST00000649966.1	c.430-10G>A		intron_variant				ENSP00000496785.1

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20211 AN: 151934 Hom.: 1376 Cov.: 33

Gnomad AFR AF: 0.0984

Gnomad AMI AF: 0.171

Gnomad AMR AF: 0.133

Gnomad ASJ AF: 0.228

Gnomad EAS AF: 0.0985

Gnomad SAS AF: 0.185

Gnomad FIN AF: 0.138

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.156

GnomAD3 exomes AF: 0.141 AC: 35411 AN: 251338 Hom.: 2758 AF XY: 0.147 AC XY: 19943 AN XY: 135852

Gnomad AFR exome AF: 0.0942

Gnomad AMR exome AF: 0.0948

Gnomad ASJ exome AF: 0.227

Gnomad EAS exome AF: 0.0961

Gnomad SAS exome AF: 0.185

Gnomad FIN exome AF: 0.139

Gnomad NFE exome AF: 0.149

Gnomad OTH exome AF: 0.159

GnomAD4 exome AF: 0.143 AC: 208752 AN: 1456800 Hom.: 15865 Cov.: 31 AF XY: 0.146 AC XY: 105694 AN XY: 725002

Gnomad4 AFR exome AF: 0.0928

Gnomad4 AMR exome AF: 0.102

Gnomad4 ASJ exome AF: 0.226

Gnomad4 EAS exome AF: 0.111

Gnomad4 SAS exome AF: 0.188

Gnomad4 FIN exome AF: 0.142

Gnomad4 NFE exome AF: 0.141

Gnomad4 OTH exome AF: 0.149

GnomAD4 genome AF: 0.133 AC: 20204 AN: 152052 Hom.: 1373 Cov.: 33 AF XY: 0.134 AC XY: 9970 AN XY: 74332

Gnomad4 AFR AF: 0.0983

Gnomad4 AMR AF: 0.133

Gnomad4 ASJ AF: 0.228

Gnomad4 EAS AF: 0.0979

Gnomad4 SAS AF: 0.185

Gnomad4 FIN AF: 0.138

Gnomad4 NFE AF: 0.146

Gnomad4 OTH AF: 0.156

Alfa AF: 0.118 Hom.: 399

Bravo AF: 0.129

Asia WGS AF: 0.137 AC: 477 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	PreventionGenetics, part of Exact Sciences	-	- -
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. -

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

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 16, 2017	Variant summary: The COL5A2 c.568-10G>A 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. However, these predictions have yet to be confirmed by functional studies. This variant was found in the large control database ExAC at a frequency of 0.1412923 (17143/121330 control chromosomes [1306 homozygotes]), which is approximately 113034 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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	-0.61
CADD	Benign	9.0
DANN	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0015
dbscSNV1_RF	Benign	0.062
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: rs58106884; hg19: chr2-189953508; COSMIC: COSV66410277;