rs372812220

chr2-189058430-T-Cchr2-189058430-T-G

Variant summary

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

The NM_000393.5(COL5A2):c.2228A>G(p.Lys743Arg) variant causes a missense, splice region 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. 2/3 splice prediction tools predicting alterations to normal splicing. 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. K743T) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense, splice_region
• Scores: Splicing: ADA: 0.9760
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.02

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 where missense usually causes diseases, COL5A2
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.2228A>G	p.Lys743Arg	missense_variant, splice_region_variant	33/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.2090A>G	p.Lys697Arg	missense_variant, splice_region_variant	36/57
COL5A2	XM_047443251.1	c.2090A>G	p.Lys697Arg	missense_variant, splice_region_variant	38/59
COL5A2	XM_047443252.1	c.2090A>G	p.Lys697Arg	missense_variant, splice_region_variant	37/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.2228A>G	p.Lys743Arg	missense_variant, splice_region_variant	33/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.1067A>G	p.Lys356Arg	missense_variant, splice_region_variant	26/47	5
COL5A2	ENST00000470524.2	n.334A>G		splice_region_variant, non_coding_transcript_exon_variant	6/8	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.44	T;T;T
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.76	D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.87	L;.;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N;.;.
REVEL	Uncertain	0.64
Sift	Benign	0.055	T;.;.
Sift4G	Benign	0.12	T;T;.
Polyphen		0.99	D;.;D
Vest4		0.42
MutPred		0.53		Loss of glycosylation at K743 (P = 0.0038);.;Loss of glycosylation at K743 (P = 0.0038);
MVP		0.86
MPC		0.21
ClinPred		0.87	D
GERP RS		5.6
Varity_R		0.16
gMVP		0.61

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.90
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

Publications

LitVar

Other links and lift over

dbSNP: rs372812220; hg19: chr2-189923156;