rs1042644306

Variant names:

• chr2-189068815-G-A
• rs1042644306
• NM_000393.5:c.1228C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189068815-G-A
• chr2-189068815-G-C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_000393.5(COL5A2):​c.1228C>T​(p.Pro410Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P410L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 7.45
• Publications: 0 publications found

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]

COL5A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 2-189068815-G-A is Benign according to our data. Variant chr2-189068815-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 392252.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1228C>T	p.Pro410Ser	missense_variant	Exon 19 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1090C>T	p.Pro364Ser	missense_variant	Exon 22 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.1090C>T	p.Pro364Ser	missense_variant	Exon 24 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.1090C>T	p.Pro364Ser	missense_variant	Exon 23 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1228C>T	p.Pro410Ser	missense_variant	Exon 19 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.359-2382C>T		intron_variant	Intron 15 of 46	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250512 AF XY: 0.00000738

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000884

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Feb 13, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

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

Jul 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.67	D;D
Eigen	Uncertain	0.21
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Uncertain	0.091	D
MetaRNN	Uncertain	0.60	D;D
MetaSVM	Pathogenic	0.92	D
MutationAssessor	Benign	1.4	L;L
PhyloP100		7.5
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.5	D;.
REVEL	Uncertain	0.40
Sift	Benign	0.071	T;.
Sift4G	Benign	0.19	T;.
Polyphen		0.21	B;B
Vest4		0.25
MutPred		0.36		Gain of phosphorylation at P410 (P = 0.0102);Gain of phosphorylation at P410 (P = 0.0102);
MVP		0.67
MPC		0.30
ClinPred		0.41	T
GERP RS		5.7
Varity_R		0.050
gMVP		0.16
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs1042644306; hg19: chr2-189933541;