chr2-189068038-G-A

Position:

• chr2-189068038-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000393.5(COL5A2):​c.1378C>T​(p.Pro460Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0454 in 1,613,706 control chromosomes in the GnomAD database, including 1,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.033 (122 hom., cov: 32)
  • Exomes 𝑓: 0.047 (1839 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 5.43

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A2. . Gene score misZ 2.4395 (greater than the threshold 3.09). Trascript score misZ 3.3523 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0034188926).
• BP6: Variant 2-189068038-G-A is Benign according to our data. Variant chr2-189068038-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189068038-G-A is described in Lovd as [Benign]. Variant chr2-189068038-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0503 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1378C>T	p.Pro460Ser	missense_variant	21/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1240C>T	p.Pro414Ser	missense_variant	24/57		XP_011508875.1
COL5A2	XM_047443251.1	c.1240C>T	p.Pro414Ser	missense_variant	26/59		XP_047299207.1
COL5A2	XM_047443252.1	c.1240C>T	p.Pro414Ser	missense_variant	25/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1378C>T	p.Pro460Ser	missense_variant	21/54	1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.359-1605C>T		intron_variant		5		ENSP00000482184

Frequencies

GnomAD3 genomes AF: 0.0328 AC: 4990 AN: 152096 Hom.: 122 Cov.: 32

Gnomad AFR AF: 0.00917

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0199

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.0172

Gnomad FIN AF: 0.0497

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0517

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0317 AC: 7951 AN: 251158 Hom.: 169 AF XY: 0.0322 AC XY: 4368 AN XY: 135726

Gnomad AFR exome AF: 0.00843

Gnomad AMR exome AF: 0.0161

Gnomad ASJ exome AF: 0.0167

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0196

Gnomad FIN exome AF: 0.0420

Gnomad NFE exome AF: 0.0476

Gnomad OTH exome AF: 0.0289

GnomAD4 exome AF: 0.0467 AC: 68255 AN: 1461492 Hom.: 1839 Cov.: 32 AF XY: 0.0459 AC XY: 33363 AN XY: 727080

Gnomad4 AFR exome AF: 0.00708

Gnomad4 AMR exome AF: 0.0166

Gnomad4 ASJ exome AF: 0.0157

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0209

Gnomad4 FIN exome AF: 0.0443

Gnomad4 NFE exome AF: 0.0542

Gnomad4 OTH exome AF: 0.0403

GnomAD4 genome AF: 0.0328 AC: 4992 AN: 152214 Hom.: 122 Cov.: 32 AF XY: 0.0316 AC XY: 2351 AN XY: 74398

Gnomad4 AFR AF: 0.00915

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.0174

Gnomad4 FIN AF: 0.0497

Gnomad4 NFE AF: 0.0517

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0430 Hom.: 261

Bravo AF: 0.0282

TwinsUK AF: 0.0647 AC: 240

ALSPAC AF: 0.0558 AC: 215

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.0543 AC: 467

ExAC AF: 0.0324 AC: 3930

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0456

EpiControl AF: 0.0441

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 27, 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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
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	-	- -

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 30, 2023	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2017	Variant summary: The COL5A2 c.1378C>T (p.Pro460Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant does not lie within a known functional domain (InterPro and UniProt) and 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0324101 (3927/121166 control chromosomes [80 homozygotes]), which is approximately 25928 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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 04, 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

Jun 10, 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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;T
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	.;D
MetaRNN	Benign	0.0034	T;T
MetaSVM	Uncertain	0.055	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	0.99	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.98	N;.
REVEL	Uncertain	0.30
Sift	Benign	0.13	T;.
Sift4G	Benign	0.29	T;.
Polyphen		0.019	B;B
Vest4		0.12
MPC		0.75
ClinPred		0.018	T
GERP RS		5.7
Varity_R		0.055
gMVP		0.053

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35830636; hg19: chr2-189932764;