NM_000393.5:c.2263A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_000393.5(COL5A2):c.2263A>C(p.Thr755Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000304 in 1,613,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. 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. T755R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 0.227

Publications

1 publications found

Variant links:

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

COL5A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.037388295).

BP6

Variant 2-189057394-T-G is Benign according to our data. Variant chr2-189057394-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 213105. Variant chr2-189057394-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 213105. Variant chr2-189057394-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 213105. Variant chr2-189057394-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 213105. Variant chr2-189057394-T-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 213105.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000165 (25/151860) while in subpopulation AFR AF = 0.00058 (24/41406). AF 95% confidence interval is 0.000399. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.2263A>C	p.Thr755Pro	missense_variant	Exon 34 of 54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.2125A>C	p.Thr709Pro	missense_variant	Exon 37 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.2125A>C	p.Thr709Pro	missense_variant	Exon 39 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.2125A>C	p.Thr709Pro	missense_variant	Exon 38 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL5A2	ENST00000374866.9 link	c.2263A>C	p.Thr755Pro	missense_variant	Exon 34 of 54	1	NM_000393.5	ENSP00000364000.3	P05997
COL5A2	ENST00000618828.1 link	c.1102A>C	p.Thr368Pro	missense_variant	Exon 27 of 47	5		ENSP00000482184.1	A0A087WYX9
COL5A2	ENST00000470524.2 link	n.369A>C		non_coding_transcript_exon_variant	Exon 7 of 8	5

Frequencies

GnomAD3 genomes

AF:

0.000165

AC:

AN:

151772

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000581

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

251378

AF XY:

0.0000147

show subpopulations

Gnomad AFR exome

AF:

0.000431

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1461738

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

727190

show subpopulations

African (AFR)

AF:

0.000627

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53396

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111902

Other (OTH)

AF:

0.0000331

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000165

AC:

AN:

151860

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74196

show subpopulations

African (AFR)

AF:

0.000580

AC:

AN:

41406

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5158

South Asian (SAS)

AF:

0.00

AC:

AN:

4800

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10510

Middle Eastern (MID)

AF:

0.00

AC:

AN:

288

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67956

Other (OTH)

AF:

0.00

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.479

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000660

Hom.:

Bravo

AF:

0.000147

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Mar 07, 2014

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome (EDS), classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011). p.Thr755Pro (ACA>CCA): c.2263 A>C in exon 34 of the COL5A2 gene (NM_000393.3). The T755P variant in the COL5A2 gene has not been reported as a disease-causing mutation or as a benign polymorphism to our knowledge. Although T755P results in a non-conservative amino acid substitution of a polar Threonine with a non-polar, sterically constrained Proline, this substitution occurs at a position that is not well conserved across species. Consequently, twoin silico analysis programs predict T755P has a benign effect on the protein structure/function, while another predicts a damaging effect. In addition, there have been no nearby mutations reported in association with classic-type EDS, indicating this region of the protein may be tolerant of change. The T755P variant was not observed with any significant frequency in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, however it was observed in 1/78 alleles (1.3%) in the dbSNP database (rs3435097). With the clinical and molecular information available at this time, we cannot definitively determine if T755P is a disease-causing mutation or a rare benign variantThis variant was found in TAAD -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Oct 30, 2024

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Dec 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.15

T;T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.76

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.60

.;T;T

M_CAP

Benign

0.068

MetaRNN

Benign

0.037

T;T;T

MetaSVM

Benign

-0.79

MutationAssessor

Benign

-0.14

N;.;N

PhyloP100

0.23

PrimateAI

Benign

0.41

PROVEAN

Benign

0.22

N;.;.

REVEL

Benign

0.24

Sift

Benign

0.37

T;.;.

Sift4G

Benign

0.34

T;T;.

Polyphen

0.0

B;.;B

Vest4

0.23

MVP

0.43

MPC

0.33

ClinPred

0.014

GERP RS

-0.89

Varity_R

0.051

gMVP

0.24

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over