rs542643688

chr2-189058868-A-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000393.5(COL5A2):c.2111T>C(p.Val704Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,613,200 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 2.62

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• BP4: Computational evidence support a benign effect (MetaRNN=0.12263802).
• BP6: Variant 2-189058868-A-G is Benign according to our data. Variant chr2-189058868-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 408287.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.2111T>C	p.Val704Ala	missense_variant	32/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.1973T>C	p.Val658Ala	missense_variant	35/57
COL5A2	XM_047443251.1	c.1973T>C	p.Val658Ala	missense_variant	37/59
COL5A2	XM_047443252.1	c.1973T>C	p.Val658Ala	missense_variant	36/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.2111T>C	p.Val704Ala	missense_variant	32/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.950T>C	p.Val317Ala	missense_variant	25/47	5
COL5A2	ENST00000470524.2	n.217T>C		non_coding_transcript_exon_variant	5/8	5

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 151422 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000437

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000660

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

GnomAD3 exomes AF: 0.0000358 AC: 9 AN: 251274 Hom.: 0 AF XY: 0.0000221 AC XY: 3 AN XY: 135836

Gnomad AFR exome AF: 0.000493

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1461660 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727146

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000125 AC: 19 AN: 151540 Hom.: 0 Cov.: 32 AF XY: 0.0000810 AC XY: 6 AN XY: 74034

Gnomad4 AFR AF: 0.000436

Gnomad4 AMR AF: 0.0000659

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

Alfa AF: 0.000125 Hom.: 0

Bravo AF: 0.000223

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 05, 2023

Has not been previously reported as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 05, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Benign	0.15	T;T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.0043
FATHMM_MKL	Uncertain	0.90	D
M_CAP	Benign	0.072	D
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	0.45	N;.;N
MutationTaster	Benign	0.98	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	0.50	N;.;.
REVEL	Benign	0.21
Sift	Benign	0.27	T;.;.
Sift4G	Benign	0.21	T;T;.
Polyphen		0.0	B;.;B
Vest4		0.35
MVP		0.24
MPC		0.31
ClinPred		0.054	T
GERP RS		5.6
Varity_R		0.043
gMVP		0.47

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: rs542643688; hg19: chr2-189923594;