rs34395097

Positions:

• chr2-189057394-T-C
• chr2-189057394-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000393.5(COL5A2):​c.2263A>G​(p.Thr755Ala) 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. 16/21 in silico tools predict a benign 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: 0.227

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 Uncertain_significance. Variant got 1 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0952906).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2263A>G	p.Thr755Ala	missense_variant	34/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.2125A>G	p.Thr709Ala	missense_variant	37/57		XP_011508875.1
COL5A2	XM_047443251.1	c.2125A>G	p.Thr709Ala	missense_variant	39/59		XP_047299207.1
COL5A2	XM_047443252.1	c.2125A>G	p.Thr709Ala	missense_variant	38/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2263A>G	p.Thr755Ala	missense_variant	34/54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.1102A>G	p.Thr368Ala	missense_variant	27/47	5		ENSP00000482184.1
COL5A2	ENST00000470524.2	n.369A>G		non_coding_transcript_exon_variant	7/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.052
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Benign	0.46
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.71
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.48	.;T;T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.095	T;T;T
MetaSVM	Benign	-0.56	T
MutationAssessor	Benign	0.73	N;.;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.64	N;.;.
REVEL	Benign	0.20
Sift	Benign	0.89	T;.;.
Sift4G	Benign	0.91	T;T;.
Polyphen		0.0	B;.;B
Vest4		0.19
MutPred		0.19		Loss of phosphorylation at T755 (P = 0.0017);.;Loss of phosphorylation at T755 (P = 0.0017);
MVP		0.57
MPC		0.25
ClinPred		0.028	T
GERP RS		-0.89
Varity_R		0.019
gMVP		0.089

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: rs34395097; hg19: chr2-189922120;