rs116298748

chr2-189053896-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PP2 PP3 BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):c.2498C>T(p.Pro833Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0204 in 1,613,182 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (23 hom., cov: 32)
  • Exomes 𝑓: 0.021 (403 hom.)
• Consequence: COL5A2 NM_000393.5 missense, splice_region
• Scores: Splicing: ADA: 0.9930
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 7.78

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 -14 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-189053896-G-A is Benign according to our data. Variant chr2-189053896-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136944.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189053896-G-A is described in Lovd as [Benign]. Variant chr2-189053896-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0153 (2329/152240) while in subpopulation NFE AF= 0.02 (1359/68010). AF 95% confidence interval is 0.0191. There are 23 homozygotes in gnomad4. There are 1144 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 2332 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.2498C>T	p.Pro833Leu	missense_variant, splice_region_variant	37/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.2360C>T	p.Pro787Leu	missense_variant, splice_region_variant	40/57
COL5A2	XM_047443251.1	c.2360C>T	p.Pro787Leu	missense_variant, splice_region_variant	42/59
COL5A2	XM_047443252.1	c.2360C>T	p.Pro787Leu	missense_variant, splice_region_variant	41/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.2498C>T	p.Pro833Leu	missense_variant, splice_region_variant	37/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.1337C>T	p.Pro446Leu	missense_variant, splice_region_variant	30/47	5

Frequencies

GnomAD3 genomes AF: 0.0153 AC: 2332 AN: 152122 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.00374

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0118

Gnomad ASJ AF: 0.0233

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0131

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0200

Gnomad OTH AF: 0.0182

GnomAD3 exomes AF: 0.0170 AC: 4270 AN: 250982 Hom.: 64 AF XY: 0.0176 AC XY: 2384 AN XY: 135688

Gnomad AFR exome AF: 0.00371

Gnomad AMR exome AF: 0.00996

Gnomad ASJ exome AF: 0.0263

Gnomad EAS exome AF: 0.000327

Gnomad SAS exome AF: 0.0125

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0212

Gnomad OTH exome AF: 0.0170

GnomAD4 exome AF: 0.0209 AC: 30601 AN: 1460942 Hom.: 403 Cov.: 31 AF XY: 0.0208 AC XY: 15118 AN XY: 726856

Gnomad4 AFR exome AF: 0.00302

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0278

Gnomad4 EAS exome AF: 0.00385

Gnomad4 SAS exome AF: 0.0135

Gnomad4 FIN exome AF: 0.0299

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0187

GnomAD4 genome AF: 0.0153 AC: 2329 AN: 152240 Hom.: 23 Cov.: 32 AF XY: 0.0154 AC XY: 1144 AN XY: 74432

Gnomad4 AFR AF: 0.00373

Gnomad4 AMR AF: 0.0117

Gnomad4 ASJ AF: 0.0233

Gnomad4 EAS AF: 0.00251

Gnomad4 SAS AF: 0.0129

Gnomad4 FIN AF: 0.0324

Gnomad4 NFE AF: 0.0200

Gnomad4 OTH AF: 0.0180

Alfa AF: 0.0197 Hom.: 43

Bravo AF: 0.0142

TwinsUK AF: 0.0237 AC: 88

ALSPAC AF: 0.0280 AC: 108

ESP6500AA AF: 0.00454 AC: 20

ESP6500EA AF: 0.0209 AC: 180

ExAC AF: 0.0170 AC: 2063

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.0220

EpiControl AF: 0.0201

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

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

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL5A2: BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 03, 2015

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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 Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics, Royal Melbourne Hospital

Jun 15, 2023

- -

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
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Uncertain	0.020
Cadd	Pathogenic	31
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D;T;D
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.014	T;T;T
MetaSVM	Uncertain	0.71	D
MutationAssessor	Uncertain	2.5	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-7.5	D;.;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.;.
Sift4G	Uncertain	0.0020	D;D;.
Polyphen		0.98	D;.;D
Vest4		0.61
MPC		0.26
ClinPred		0.027	T
GERP RS		5.9
Varity_R		0.67
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.84
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: rs116298748; hg19: chr2-189918622;