rs377331666

Positions:

• chr2-189098740-C-G
• chr2-189098740-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The ENST00000374866.9(COL5A2):​c.389G>C​(p.Arg130Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign 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. R130C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 ENST00000374866.9 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.77

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 2 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=0.36887205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.389G>C	p.Arg130Pro	missense_variant	5/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.251G>C	p.Arg84Pro	missense_variant	8/57		XP_011508875.1
COL5A2	XM_047443251.1	c.251G>C	p.Arg84Pro	missense_variant	10/59		XP_047299207.1
COL5A2	XM_047443252.1	c.251G>C	p.Arg84Pro	missense_variant	9/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.389G>C	p.Arg130Pro	missense_variant	5/54	1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000649966.1	c.251G>C	p.Arg84Pro	missense_variant	5/11			ENSP00000496785
COL5A2	ENST00000618828.1	c.-242G>C		5_prime_UTR_variant	5/47	5		ENSP00000482184

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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	0.32
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.34	T;T;.
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.37	T;T;T
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	-1.1	N;N;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	0.38	N;.;.
REVEL	Uncertain	0.44
Sift	Benign	0.45	T;.;.
Sift4G	Benign	1.0	T;.;.
Polyphen		1.0	D;D;.
Vest4		0.64
MutPred		0.51		Loss of methylation at R130 (P = 0.0069);Loss of methylation at R130 (P = 0.0069);.;
MVP		0.73
MPC		1.1
ClinPred		0.92	D
GERP RS		5.6
Varity_R		0.25
gMVP		0.79

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: rs377331666; hg19: chr2-189963466;