rs886039694

Variant names:

• chr2-189052945-C-G
• rs886039694
• NM_000393.5:c.2627G>C

Your query was ambiguous. Multiple possible variants found:

• chr2-189052945-C-G
• chr2-189052945-C-T

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PM5 PP3_Strong

The NM_000393.5(COL5A2):​c.2627G>C​(p.Gly876Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,828 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/22 in silico tools predict a damaging outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G876E) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-189052945-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 265645.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2627G>C	p.Gly876Ala	missense_variant	Exon 39 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.2489G>C	p.Gly830Ala	missense_variant	Exon 42 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.2489G>C	p.Gly830Ala	missense_variant	Exon 44 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.2489G>C	p.Gly830Ala	missense_variant	Exon 43 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2627G>C	p.Gly876Ala	missense_variant	Exon 39 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.1466G>C	p.Gly489Ala	missense_variant	Exon 32 of 47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53408

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.58	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.90	D;T;D
Eigen	Pathogenic	0.99
Eigen_PC	Pathogenic	0.90
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	.;D;D
M_CAP	Pathogenic	0.44	D
MetaRNN	Pathogenic	0.99	D;D;D
MetaSVM	Pathogenic	0.99	D
MutationAssessor	Pathogenic	3.8	H;.;H
PhyloP100		7.9
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-5.5	D;.;.
REVEL	Pathogenic	0.99
Sift	Pathogenic	0.0	D;.;.
Sift4G	Pathogenic	0.0	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.99
MutPred		0.99		Loss of catalytic residue at G876 (P = 0.0337);.;Loss of catalytic residue at G876 (P = 0.0337);
MVP		0.98
MPC		0.28
ClinPred		0.99	D
GERP RS		5.3
Varity_R		0.89
gMVP		0.97
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs886039694; hg19: chr2-189917671;