rs745845130

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2

The NM_000393.5(COL5A2):c.3567C>A(p.Asn1189Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000657 in 1,613,964 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000068 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.685

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.15700558).

BP6

Variant 2-189041652-G-T is Benign according to our data. Variant chr2-189041652-G-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 561292.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

BS2

High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
COL5A2	NM_000393.5 linkuse as main transcript	c.3567C>A	p.Asn1189Lys	missense_variant	50/54	ENST00000374866.9
COL5A2	XM_011510573.4 linkuse as main transcript	c.3429C>A	p.Asn1143Lys	missense_variant	53/57
COL5A2	XM_047443251.1 linkuse as main transcript	c.3429C>A	p.Asn1143Lys	missense_variant	55/59
COL5A2	XM_047443252.1 linkuse as main transcript	c.3429C>A	p.Asn1143Lys	missense_variant	54/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9 linkuse as main transcript	c.3567C>A	p.Asn1189Lys	missense_variant	50/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1 linkuse as main transcript	c.2406C>A	p.Asn802Lys	missense_variant	43/47	5

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000278

AC:

AN:

251414

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135880

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

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:

0.0000528

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000684

AC:

100

AN:

1461784

Hom.:

Cov.:

AF XY:

0.0000605

AC XY:

AN XY:

727198

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000800

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152180

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.0000340

ExAC

AF:

0.0000165

AC:

EpiCase

AF:

0.000109

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 31, 2024

The p.N1189K variant (also known as c.3567C>A), located in coding exon 50 of the COL5A2 gene, results from a C to A substitution at nucleotide position 3567. The asparagine at codon 1189 is replaced by lysine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Feb 15, 2022

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 27, 2023

- -

Connective tissue disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.29

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.24

Cadd

Benign

Dann

Benign

0.72

DEOGEN2

Uncertain

0.47

T;T;T

Eigen

Benign

-0.55

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.94

M_CAP

Benign

0.053

MetaRNN

Benign

0.16

T;T;T

MetaSVM

Benign

-0.41

MutationAssessor

Benign

-0.27

N;.;N

MutationTaster

Benign

0.92

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.65

N;.;.

REVEL

Benign

0.26

Sift

Benign

0.38

T;.;.

Sift4G

Benign

0.73

T;T;.

Polyphen

0.42

B;.;B

Vest4

0.35

MutPred

0.55

Gain of methylation at N1189 (P = 0.0073);.;Gain of methylation at N1189 (P = 0.0073);

MVP

0.66

MPC

0.30

ClinPred

0.082

GERP RS

1.9

Varity_R

0.043

gMVP

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over