2-189062869-G-A

Position:

• chr2-189062869-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PP2 PP3_Moderate BP6 BS2

The NM_000393.5(COL5A2):​c.1973C>T​(p.Pro658Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,802 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).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 9.82

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]

COL5A2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877
• BP6: Variant 2-189062869-G-A is Benign according to our data. Variant chr2-189062869-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 529278.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1973C>T	p.Pro658Leu	missense_variant	29/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1835C>T	p.Pro612Leu	missense_variant	32/57		XP_011508875.1
COL5A2	XM_047443251.1	c.1835C>T	p.Pro612Leu	missense_variant	34/59		XP_047299207.1
COL5A2	XM_047443252.1	c.1835C>T	p.Pro612Leu	missense_variant	33/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1973C>T	p.Pro658Leu	missense_variant	29/54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.812C>T	p.Pro271Leu	missense_variant	22/47	5		ENSP00000482184.1
COL5A2	ENST00000470524.2	n.79C>T		non_coding_transcript_exon_variant	2/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000797 AC: 2 AN: 250960 Hom.: 0 AF XY: 0.0000147 AC XY: 2 AN XY: 135612

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461802 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000812

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 26, 2024

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 19, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;T;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Pathogenic	0.88	D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Benign	1.2	L;.;L
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-5.9	D;.;.
REVEL	Pathogenic	0.81
Sift	Benign	0.057	T;.;.
Sift4G	Uncertain	0.043	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.71
MutPred		0.50		Loss of glycosylation at P658 (P = 0.1088);.;Loss of glycosylation at P658 (P = 0.1088);
MVP		0.85
MPC		0.92
ClinPred		0.90	D
GERP RS		4.7
Varity_R		0.18
gMVP		0.37

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: rs746458284; hg19: chr2-189927595; COSMIC: COSV100880995;