rs372812220

Variant names:

• chr2-189058430-T-C
• rs372812220
• NM_000393.5:c.2228A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-189058430-T-C
• chr2-189058430-T-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 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 Likely benign.

• 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
• Publications: 0 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.2228A>G	p.Lys743Arg	missense splice_region	Exon 33 of 54	NP_000384.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.2228A>G	p.Lys743Arg	missense splice_region	Exon 33 of 54	ENSP00000364000.3
	COL5A2	ENST00000618828.1	TSL:5	c.1067A>G	p.Lys356Arg	missense splice_region	Exon 26 of 47	ENSP00000482184.1
	COL5A2	ENST00000470524.2	TSL:5	n.334A>G		splice_region non_coding_transcript_exon	Exon 6 of 8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Benign	0.87	L
PhyloP100		8.0
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.64
Sift	Benign	0.055	T
Sift4G	Benign	0.12	T
Polyphen		0.99	D
Vest4		0.42
MutPred		0.53		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
Mutation Taster		=70/30	polymorphism

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

Other links and lift over

dbSNP: rs372812220; hg19: chr2-189923156;