rs754751410

Positions:

• chr2-189051388-C-A
• chr2-189051388-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_000393.5(COL5A2):​c.2863G>T​(p.Asp955Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.90

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2863G>T	p.Asp955Tyr	missense_variant	42/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.2725G>T	p.Asp909Tyr	missense_variant	45/57		XP_011508875.1
COL5A2	XM_047443251.1	c.2725G>T	p.Asp909Tyr	missense_variant	47/59		XP_047299207.1
COL5A2	XM_047443252.1	c.2725G>T	p.Asp909Tyr	missense_variant	46/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2863G>T	p.Asp955Tyr	missense_variant	42/54	1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.1702G>T	p.Asp568Tyr	missense_variant	35/47	5		ENSP00000482184

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;T;D
Eigen	Uncertain	0.66
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.95	.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	2.0	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.9	D;.;.
REVEL	Uncertain	0.60
Sift	Uncertain	0.0020	D;.;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.61
MutPred		0.46		Gain of phosphorylation at D955 (P = 0.011);.;Gain of phosphorylation at D955 (P = 0.011);
MVP		0.75
MPC		0.32
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.35
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-189916114;