2-189053010-G-C

Position:

• chr2-189053010-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_000393.5(COL5A2):​c.2562C>G​(p.Asp854Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000658 in 152,052 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. D854D) has been classified as Benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.23

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2562C>G	p.Asp854Glu	missense_variant	39/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.2424C>G	p.Asp808Glu	missense_variant	42/57		XP_011508875.1
COL5A2	XM_047443251.1	c.2424C>G	p.Asp808Glu	missense_variant	44/59		XP_047299207.1
COL5A2	XM_047443252.1	c.2424C>G	p.Asp808Glu	missense_variant	43/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2562C>G	p.Asp854Glu	missense_variant	39/54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.1401C>G	p.Asp467Glu	missense_variant	32/47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 152052 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74268

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.66	D;T;D
Eigen	Benign	-0.17
Eigen_PC	Benign	-0.18
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.48	T;T;T
MetaSVM	Uncertain	0.19	D
MutationAssessor	Benign	0.63	N;.;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.9	N;.;.
REVEL	Uncertain	0.54
Sift	Benign	0.066	T;.;.
Sift4G	Benign	0.36	T;T;.
Polyphen		0.99	D;.;D
Vest4		0.49
MutPred		0.22		Gain of solvent accessibility (P = 0.3089);.;Gain of solvent accessibility (P = 0.3089);
MVP		0.94
MPC		0.24
ClinPred		0.62	D
GERP RS		-0.14
Varity_R		0.074
gMVP		0.39

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: rs148430780; hg19: chr2-189917736;