rs7586

Positions:

• chr2-189033772-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.*298G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0522 in 396,392 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.069 (473 hom., cov: 32)
  • Exomes 𝑓: 0.042 (308 hom.)
• Consequence: COL5A2 NM_000393.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0750

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=-0.78).
• BP6: Variant 2-189033772-C-T is Benign according to our data. Variant chr2-189033772-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 333126.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.135 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.*298G>A		3_prime_UTR_variant	54/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.*298G>A		3_prime_UTR_variant	57/57		XP_011508875.1
COL5A2	XM_047443251.1	c.*298G>A		3_prime_UTR_variant	59/59		XP_047299207.1
COL5A2	XM_047443252.1	c.*298G>A		3_prime_UTR_variant	58/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.*298G>A		3_prime_UTR_variant	54/54	1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.*298G>A		3_prime_UTR_variant	47/47	5		ENSP00000482184

Frequencies

GnomAD3 genomes AF: 0.0687 AC: 10435 AN: 151888 Hom.: 466 Cov.: 32

Gnomad AFR AF: 0.138

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0455

Gnomad ASJ AF: 0.0590

Gnomad EAS AF: 0.00405

Gnomad SAS AF: 0.0284

Gnomad FIN AF: 0.0482

Gnomad MID AF: 0.0665

Gnomad NFE AF: 0.0431

Gnomad OTH AF: 0.0679

GnomAD4 exome AF: 0.0418 AC: 10221 AN: 244386 Hom.: 308 Cov.: 2 AF XY: 0.0402 AC XY: 5183 AN XY: 128950

Gnomad4 AFR exome AF: 0.138

Gnomad4 AMR exome AF: 0.0461

Gnomad4 ASJ exome AF: 0.0612

Gnomad4 EAS exome AF: 0.00470

Gnomad4 SAS exome AF: 0.0261

Gnomad4 FIN exome AF: 0.0438

Gnomad4 NFE exome AF: 0.0413

Gnomad4 OTH exome AF: 0.0465

GnomAD4 genome AF: 0.0689 AC: 10467 AN: 152006 Hom.: 473 Cov.: 32 AF XY: 0.0683 AC XY: 5076 AN XY: 74308

Gnomad4 AFR AF: 0.138

Gnomad4 AMR AF: 0.0453

Gnomad4 ASJ AF: 0.0590

Gnomad4 EAS AF: 0.00406

Gnomad4 SAS AF: 0.0284

Gnomad4 FIN AF: 0.0482

Gnomad4 NFE AF: 0.0431

Gnomad4 OTH AF: 0.0672

Alfa AF: 0.0664 Hom.: 85

Bravo AF: 0.0721

Asia WGS AF: 0.0240 AC: 82 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Ehlers-Danlos syndrome, classic type, 2 Benign:1

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. -

Ehlers-Danlos syndrome type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	10
DANN	Benign	0.72

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: rs7586; hg19: chr2-189898498;