NM_000393.5:c.1175C>T

Variant names:

• chr2-189068868-G-A
• rs1553515880
• NM_000393.5:c.1175C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_000393.5(COL5A2):​c.1175C>T​(p.Thr392Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,234 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.25
• 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.1175C>T	p.Thr392Ile	missense	Exon 19 of 54	NP_000384.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.1175C>T	p.Thr392Ile	missense	Exon 19 of 54	ENSP00000364000.3
	COL5A2	ENST00000858728.1		c.1172C>T	p.Thr391Ile	missense	Exon 19 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.1175C>T	p.Thr392Ile	missense	Exon 19 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460234 Hom.: 0 Cov.: 30 AF XY: 0.00000551 AC XY: 4 AN XY: 726480

African (AFR) AF: 0.00 AC: 0 AN: 33440

American (AMR) AF: 0.00 AC: 0 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53310

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5370

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111108

Other (OTH) AF: 0.00 AC: 0 AN: 60292

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, classic type, 1 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.46	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D
M_CAP	Uncertain	0.15	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Uncertain	0.35	D
MutationAssessor	Benign	0.48	N
PhyloP100		6.3
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.43
Sift	Benign	0.085	T
Sift4G	Benign	0.40	T
Polyphen		0.94	P
Vest4		0.41
MutPred		0.28		Loss of phosphorylation at T392 (P = 0.0036)
MVP		0.61
MPC		0.95
ClinPred		0.70	D
GERP RS		5.7
Varity_R		0.094
gMVP		0.51
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs1553515880; hg19: chr2-189933594;