rs762874073

Positions:

• chr2-189179600-A-G

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2 BS2

The NM_000393.5(COL5A2):​c.5T>C​(p.Met2Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000281 in 1,603,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 5.72

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 -3 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL5A2
• BS2: High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.5T>C	p.Met2Thr	missense_variant	1/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.-42+45548T>C		intron_variant
COL5A2	XM_047443251.1	c.-42+45548T>C		intron_variant
COL5A2	XM_047443252.1	c.-42+45548T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.5T>C	p.Met2Thr	missense_variant	1/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.-626T>C		5_prime_UTR_variant	1/47	5
COL5A2	ENST00000649966.1	c.-42+45548T>C		intron_variant

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000469 AC: 11 AN: 234428 Hom.: 0 AF XY: 0.0000713 AC XY: 9 AN XY: 126228

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000106

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000871

Gnomad OTH exome AF: 0.000172

GnomAD4 exome AF: 0.0000303 AC: 44 AN: 1451056 Hom.: 0 Cov.: 31 AF XY: 0.0000347 AC XY: 25 AN XY: 720802

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000390

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000569

Gnomad4 NFE exome AF: 0.0000344

Gnomad4 OTH exome AF: 0.0000334

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152186 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 74350

Gnomad4 AFR AF: 0.00

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: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	Reported in a patient with classic Ehlers-Danlos syndrome who also harbored the p.(P659L) variant in COL5A2 (PMID: 33161638); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); This variant is associated with the following publications: (PMID: 22696272, 33161638) -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 11, 2020	- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2019

The p.M2T variant (also known as c.5T>C), located in coding exon 1 of the COL5A2 gene, results from a T to C substitution at nucleotide position 5. The methionine at codon 2 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Pathogenic	0.20
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.86	D
M_CAP	Benign	0.075	D
MetaRNN	Uncertain	0.70	D;D
MetaSVM	Uncertain	0.081	D
MutationAssessor	Benign	0.0	N;N
MutationTaster	Benign	0.86	D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-1.4	N;.
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Polyphen		0.72	P;P
Vest4		0.78
MutPred		0.47		Gain of glycosylation at M2 (P = 0.0099);Gain of glycosylation at M2 (P = 0.0099);
MVP		0.96
MPC		0.37
ClinPred		0.26	T
GERP RS		4.8
Varity_R		0.85
gMVP		0.68

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: rs762874073; hg19: chr2-190044326;