rs200839338

Variant names:

• chr2-189068267-C-A
• rs200839338
• NM_000393.5:c.1261G>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189068267-C-A
• chr2-189068267-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000393.5(COL5A2):​c.1261G>T​(p.Ala421Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A421T) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.154
• Publications: 3 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08276883).

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.1261G>T	p.Ala421Ser	missense	Exon 20 of 54	NP_000384.2	P05997

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.1261G>T	p.Ala421Ser	missense	Exon 20 of 54	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.1258G>T	p.Ala420Ser	missense	Exon 20 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.1261G>T	p.Ala421Ser	missense	Exon 20 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.70
FATHMM_MKL	Benign	0.30	N
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	0.67	N
PhyloP100		0.15
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.46	N
REVEL	Benign	0.20
Sift	Benign	0.40	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.28		Gain of glycosylation at A421 (P = 0.0053)
MVP		0.27
MPC		0.34
ClinPred		0.049	T
GERP RS		-1.1
Varity_R		0.022
gMVP		0.039
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs200839338; hg19: chr2-189932993;