rs73978832

chr2-189078578-G-Achr2-189078578-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):c.1006-9C>T variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,608,904 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.021 (391 hom.)
• Consequence: COL5A2 NM_000393.5 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002179
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.16

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=-0.88).
• BP6: Variant 2-189078578-G-A is Benign according to our data. Variant chr2-189078578-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136933.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189078578-G-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0154 (2348/152150) while in subpopulation NFE AF= 0.02 (1363/67996). AF 95% confidence interval is 0.0192. There are 24 homozygotes in gnomad4. There are 1156 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2351 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.1006-9C>T		splice_polypyrimidine_tract_variant, intron_variant		ENST00000374866.9
COL5A2	XM_011510573.4	c.868-9C>T		splice_polypyrimidine_tract_variant, intron_variant
COL5A2	XM_047443251.1	c.868-9C>T		splice_polypyrimidine_tract_variant, intron_variant
COL5A2	XM_047443252.1	c.868-9C>T		splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.1006-9C>T		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.358+502C>T		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2351 AN: 152032 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0171 AC: 4305 AN: 251310 Hom.: 67 AF XY: 0.0176 AC XY: 2396 AN XY: 135816

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00999

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0206 AC: 30032 AN: 1456754 Hom.: 391 Cov.: 30 AF XY: 0.0205 AC XY: 14840 AN XY: 724970

Gnomad4 AFR exome AF: 0.00327

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0276

Gnomad4 EAS exome AF: 0.00388

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0222

Gnomad4 OTH exome AF: 0.0184

GnomAD4 genome AF: 0.0154 AC: 2348 AN: 152150 Hom.: 24 Cov.: 32 AF XY: 0.0155 AC XY: 1156 AN XY: 74370

Gnomad4 AFR AF: 0.00395

Gnomad4 AMR AF: 0.0118

Gnomad4 ASJ AF: 0.0234

Gnomad4 EAS AF: 0.00271

Gnomad4 SAS AF: 0.0137

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0183 Hom.: 8

Bravo AF: 0.0143

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 11, 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	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 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. -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	2.8
Dann	Benign	0.51

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
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: rs73978832; hg19: chr2-189943304; COSMIC: COSV104425976;