rs144602736

Positions:

• chr2-189068236-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP6 BS2

The NM_000393.5(COL5A2):​c.1292A>G​(p.Lys431Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000167 in 1,613,836 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:8 B:2
• Conservation: PhyloP100: 4.63

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 Likely_benign. Variant got -4 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.
• BP6: Variant 2-189068236-T-C is Benign according to our data. Variant chr2-189068236-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213094.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=7}.
• BS2: High AC in GnomAd4 at 16 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1292A>G	p.Lys431Arg	missense_variant	20/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1154A>G	p.Lys385Arg	missense_variant	23/57		XP_011508875.1
COL5A2	XM_047443251.1	c.1154A>G	p.Lys385Arg	missense_variant	25/59		XP_047299207.1
COL5A2	XM_047443252.1	c.1154A>G	p.Lys385Arg	missense_variant	24/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1292A>G	p.Lys431Arg	missense_variant	20/54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.359-1803A>G		intron_variant		5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000557 AC: 14 AN: 251198 Hom.: 0 AF XY: 0.0000737 AC XY: 10 AN XY: 135746

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000173 AC: 253 AN: 1461662 Hom.: 0 Cov.: 31 AF XY: 0.000151 AC XY: 110 AN XY: 727162

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000221

Gnomad4 OTH exome AF: 0.0000994

GnomAD4 genome AF: 0.000105 AC: 16 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74336

Gnomad4 AFR AF: 0.000121

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.000479

Alfa AF: 0.000216 Hom.: 5

Bravo AF: 0.0000945

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.0000659 AC: 8

EpiCase AF: 0.000327

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:8 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:5

Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 31, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function; Reported in ClinVar as a variant of uncertain significance (ClinVar Variant ID# 213094; Landrum et al., 2016) -
Uncertain significance, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	The COL5A2 p.Lys431Arg variant was not identified in the literature but was identified in dbSNP (ID: rs144602736) and ClinVar (classified as uncertain significance by Invitae, GeneDx, Illumina, ARUP Laboratories, and CeGaT Praxis). The variant was identified in control databases in 15 of 282602 chromosomes at a frequency of 0.00005308 (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 13 of 128958 chromosomes (freq: 0.000101) and African in 2 of 24970 chromosomes (freq: 0.00008), but was not observed in the Latino, Ashkenazi Jewish, East Asian, European (Finnish), Other, or South Asian populations. The p.Lys431 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. The variant occurs outside of the splicing consensus sequence and three of four in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 06, 2023	BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 16, 2018	The COL5A2 c.1292A>G; p.Lys431Arg variant (rs144602736), to our knowledge, is not reported in the medical literature, gene specific variation databases, nor has it been previously identified by our laboratory. This variant is listed in the genome Aggregation Database (gnomAD) with an overall population frequency of 0.006% (identified on 14 out of 245,942 chromosomes) and is classified as a variant of unknown significance in ClinVar (ID: 213094). The lysine at position 431 is highly conserved, considering 12 species, and computational analyses of the effects of the p.Lys431Arg variant on protein structure and function provide conflicting predictions (SIFT: tolerated, PolyPhen-2: possibly damaging ). Based on the available information, the clinical significance of the p.Lys431Arg variant cannot be determined with certainty. -

COL5A2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2023

The COL5A2 c.1292A>G variant is predicted to result in the amino acid substitution p.Lys431Arg. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.010% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-189932962-T-C). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2021

The p.K431R variant (also known as c.1292A>G), located in coding exon 20 of the COL5A2 gene, results from an A to G substitution at nucleotide position 1292. The lysine at codon 431 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Ehlers-Danlos syndrome type 7A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 07, 2023

Variant summary: COL5A2 c.1292A>G (p.Lys431Arg) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251198 control chromosomes. The observed variant frequency is approximately 8.9 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A2 causing Ehlers-Danlos Syndrome phenotype (6.3e-06), suggesting that the variant is benign. To our knowledge, no occurrence of c.1292A>G in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Seven submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 (VUS, n=6; Likely Benign, n=1). Based on the evidence outlined above, the variant was classified as likely benign. -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 29, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.036	T
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T;T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.79	.;T
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Uncertain	0.62	D
MutationAssessor	Benign	0.24	N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.1	N;.
REVEL	Uncertain	0.60
Sift	Benign	0.083	T;.
Sift4G	Uncertain	0.0050	D;.
Polyphen		0.92	P;P
Vest4		0.42
MVP		0.84
MPC		0.80
ClinPred		0.21	T
GERP RS		5.2
Varity_R		0.13
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs144602736; hg19: chr2-189932962;