chr2-189083970-G-A

Variant names:

• chr2-189083970-G-A
• rs56310996
• NM_000393.5:c.852+14C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId is 136971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.852+14C>T		intron	N/A	NP_000384.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.852+14C>T		intron	N/A	ENSP00000364000.3
	COL5A2	ENST00000618828.1	TSL:5	c.222+14C>T		intron	N/A	ENSP00000482184.1

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

GnomAD2 exomes AF: 0.143 AC: 35962 AN: 251038 AF XY: 0.148

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 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

African (AFR) AF: 0.123 AC: 4051 AN: 33044

American (AMR) AF: 0.104 AC: 4668 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.225 AC: 5846 AN: 25948

East Asian (EAS) AF: 0.111 AC: 4403 AN: 39544

South Asian (SAS) AF: 0.188 AC: 16085 AN: 85730

European-Finnish (FIN) AF: 0.141 AC: 7538 AN: 53304

Middle Eastern (MID) AF: 0.245 AC: 1404 AN: 5728

European-Non Finnish (NFE) AF: 0.140 AC: 153625 AN: 1094592

Other (OTH) AF: 0.150 AC: 8949 AN: 59708

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

African (AFR) AF: 0.131 AC: 5429 AN: 41474

American (AMR) AF: 0.136 AC: 2072 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.228 AC: 790 AN: 3472

East Asian (EAS) AF: 0.0978 AC: 506 AN: 5172

South Asian (SAS) AF: 0.185 AC: 893 AN: 4824

European-Finnish (FIN) AF: 0.138 AC: 1456 AN: 10570

Middle Eastern (MID) AF: 0.190 AC: 56 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9917 AN: 67982

Other (OTH) AF: 0.158 AC: 335 AN: 2114

Alfa AF: 0.152 Hom.: 366

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 16, 2012

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Mar 15, 2017

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

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.7
DANN	Benign	0.27
PhyloP100		-0.10
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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