rs775697182

chr2-189036754-T-Achr2-189036754-T-C

Variant summary

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

The NM_000393.5(COL5A2):c.3975A>T(p.Lys1325Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,446 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. K1325K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.25

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 where missense usually causes diseases, COL5A2

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.3975A>T	p.Lys1325Asn	missense_variant	52/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.3837A>T	p.Lys1279Asn	missense_variant	55/57
COL5A2	XM_047443251.1	c.3837A>T	p.Lys1279Asn	missense_variant	57/59
COL5A2	XM_047443252.1	c.3837A>T	p.Lys1279Asn	missense_variant	56/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.3975A>T	p.Lys1325Asn	missense_variant	52/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.2814A>T	p.Lys938Asn	missense_variant	45/47	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250746 Hom.: 0 AF XY: 0.00000738 AC XY: 1 AN XY: 135564

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461446 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727020

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: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Benign	-0.048	T
BayesDel_noAF	Benign	-0.21
Cadd	Benign	23
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.63	D;T;D
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.037	D
MetaRNN	Uncertain	0.54	D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Pathogenic	3.5	M;.;M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-3.2	D;.;.
REVEL	Uncertain	0.61
Sift	Uncertain	0.021	D;.;.
Sift4G	Uncertain	0.0030	D;D;.
Polyphen		1.0	D;.;D
Vest4		0.57
MutPred		0.56		Loss of methylation at K1325 (P = 0.0057);.;Loss of methylation at K1325 (P = 0.0057);
MVP		0.83
MPC		0.30
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.82

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: rs775697182; hg19: chr2-189901480;