rs753383064

chr2-189039529-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PP2 PP3 BP6 BS2

The NM_000393.5(COL5A2):c.3668C>T(p.Pro1223Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000242 in 1,613,762 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P1223P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 10.0

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 -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.792
• BP6: Variant 2-189039529-G-A is Benign according to our data. Variant chr2-189039529-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 333131.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS2: High AC in GnomAdExome at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.3668C>T	p.Pro1223Leu	missense_variant	51/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.3530C>T	p.Pro1177Leu	missense_variant	54/57
COL5A2	XM_047443251.1	c.3530C>T	p.Pro1177Leu	missense_variant	56/59
COL5A2	XM_047443252.1	c.3530C>T	p.Pro1177Leu	missense_variant	55/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.3668C>T	p.Pro1223Leu	missense_variant	51/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.2507C>T	p.Pro836Leu	missense_variant	44/47	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152108 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000201 AC: 5 AN: 249354 Hom.: 0 AF XY: 0.0000296 AC XY: 4 AN XY: 135156

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000888

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000239 AC: 35 AN: 1461654 Hom.: 0 Cov.: 32 AF XY: 0.0000165 AC XY: 12 AN XY: 727128

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000327

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000135

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152108 Hom.: 0 Cov.: 31 AF XY: 0.0000404 AC XY: 3 AN XY: 74314

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.0000340

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Ehlers-Danlos syndrome type 7A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

May 22, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Pathogenic	0.14
Cadd	Pathogenic	30
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.92	D;T;D
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.79	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Uncertain	2.7	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-8.5	D;.;.
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;.;.
Sift4G	Pathogenic	0.0010	D;D;.
Polyphen		0.98	D;.;D
Vest4		0.63
MutPred		0.40		Loss of glycosylation at P1223 (P = 0.0042);.;Loss of glycosylation at P1223 (P = 0.0042);
MVP		0.81
MPC		0.26
ClinPred		0.80	D
GERP RS		5.3
Varity_R		0.57
gMVP		0.69

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: rs753383064; hg19: chr2-189904255; COSMIC: COSV66407675;