2-189110374-G-A

Variant names:

• chr2-189110374-G-A
• rs766925699
• NM_000393.5:c.173C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 4P and 4B. PM2 PP3_Moderate BS1

The NM_000393.5(COL5A2):​c.173C>T​(p.Pro58Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,856 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic 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. P58H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (1 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.85

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.856
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00000274 (4/1461856) while in subpopulation SAS AF= 0.0000464 (4/86256). AF 95% confidence interval is 0.0000158. There are 1 homozygotes in gnomad4_exome. There are 3 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.173C>T	p.Pro58Leu	missense_variant	Exon 2 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.35C>T	p.Pro12Leu	missense_variant	Exon 5 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.35C>T	p.Pro12Leu	missense_variant	Exon 7 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.35C>T	p.Pro12Leu	missense_variant	Exon 6 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.173C>T	p.Pro58Leu	missense_variant	Exon 2 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000649966.1	c.35C>T	p.Pro12Leu	missense_variant	Exon 2 of 11			ENSP00000496785.1
COL5A2	ENST00000618828.1	c.-458C>T		5_prime_UTR_variant	Exon 2 of 47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000796 AC: 2 AN: 251380 Hom.: 1 AF XY: 0.0000147 AC XY: 2 AN XY: 135846

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461856 Hom.: 1 Cov.: 33 AF XY: 0.00000413 AC XY: 3 AN XY: 727228

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.14
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T;T;.
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Benign	0.49	N
LIST_S2	Uncertain	0.96	.;D;D
M_CAP	Uncertain	0.085	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.8	D;.;.
REVEL	Uncertain	0.44
Sift	Uncertain	0.0060	D;.;.
Sift4G	Uncertain	0.0080	D;.;.
Polyphen		0.95	P;P;.
Vest4		0.55
MutPred		0.82		Loss of sheet (P = 0.0357);Loss of sheet (P = 0.0357);.;
MVP		0.53
MPC		0.75
ClinPred		0.86	D
GERP RS		4.5
Varity_R		0.24
gMVP		0.77

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: rs766925699; hg19: chr2-189975100;