2-189039508-G-C

Position:

chr2-189039508-G-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The ENST00000374866.9(COL5A2):c.3689C>G(p.Thr1230Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00756 in 1,614,060 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1230A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0058 ( 5 hom., cov: 31)

Exomes 𝑓: 0.0077 ( 59 hom. )

Consequence

COL5A2
ENST00000374866.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.66

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 Benign. Variant got -19 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A2. . Gene score misZ 2.4395 (greater than the threshold 3.09). Trascript score misZ 3.3523 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type.

BP4

Computational evidence support a benign effect (MetaRNN=0.0091317).

BP6

Variant 2-189039508-G-C is Benign according to our data. Variant chr2-189039508-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 136952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189039508-G-C is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00578 (881/152300) while in subpopulation NFE AF= 0.00979 (666/68020). AF 95% confidence interval is 0.00917. There are 5 homozygotes in gnomad4. There are 400 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 881 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL5A2	NM_000393.5 linkuse as main transcript	c.3689C>G	p.Thr1230Arg	missense_variant	51/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4 linkuse as main transcript	c.3551C>G	p.Thr1184Arg	missense_variant	54/57		XP_011508875.1
COL5A2	XM_047443251.1 linkuse as main transcript	c.3551C>G	p.Thr1184Arg	missense_variant	56/59		XP_047299207.1
COL5A2	XM_047443252.1 linkuse as main transcript	c.3551C>G	p.Thr1184Arg	missense_variant	55/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 linkuse as main transcript	c.3689C>G	p.Thr1230Arg	missense_variant	51/54	1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1 linkuse as main transcript	c.2528C>G	p.Thr843Arg	missense_variant	44/47	5		ENSP00000482184

Frequencies

GnomAD3 genomes

AF:

0.00579

AC:

881

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.00537

Gnomad ASJ

AF:

0.000576

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.00367

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00979

Gnomad OTH

AF:

0.00431

GnomAD3 exomes

AF:

0.00487

AC:

1221

AN:

250610

Hom.:

AF XY:

0.00509

AC XY:

690

AN XY:

135574

show subpopulations

Gnomad AFR exome

AF:

0.00144

Gnomad AMR exome

AF:

0.00260

Gnomad ASJ exome

AF:

0.000894

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00180

Gnomad FIN exome

AF:

0.00379

Gnomad NFE exome

AF:

0.00825

Gnomad OTH exome

AF:

0.00441

GnomAD4 exome

AF:

0.00774

AC:

11318

AN:

1461760

Hom.:

Cov.:

AF XY:

0.00751

AC XY:

5463

AN XY:

727182

show subpopulations

Gnomad4 AFR exome

AF:

0.00119

Gnomad4 AMR exome

AF:

0.00304

Gnomad4 ASJ exome

AF:

0.00130

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00176

Gnomad4 FIN exome

AF:

0.00391

Gnomad4 NFE exome

AF:

0.00933

Gnomad4 OTH exome

AF:

0.00599

GnomAD4 genome

AF:

0.00578

AC:

881

AN:

152300

Hom.:

Cov.:

AF XY:

0.00537

AC XY:

400

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00536

Gnomad4 ASJ

AF:

0.000576

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00186

Gnomad4 FIN

AF:

0.00367

Gnomad4 NFE

AF:

0.00979

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00499

Hom.:

Bravo

AF:

0.00603

TwinsUK

AF:

0.0135

AC:

ALSPAC

AF:

0.0104

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00779

AC:

ExAC

AF:

0.00456

AC:

554

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.00714

EpiControl

AF:

0.00705

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 23, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jun 20, 2017	- -

Ehlers-Danlos syndrome, classic type, 2

Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL5A2: BS2 -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2015

This alteration is classified as 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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 12, 2022

- -

Ehlers-Danlos syndrome type 7A

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome, classic type

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Nov 01, 2016

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.46

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.34

T;T;T

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.36

FATHMM_MKL

Uncertain

0.96

LIST_S2

Benign

0.76

.;T;T

M_CAP

Benign

0.045

MetaRNN

Benign

0.0091

T;T;T

MetaSVM

Uncertain

-0.16

MutationAssessor

Benign

1.2

L;.;L

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.70

PROVEAN

Benign

-1.5

N;.;.

REVEL

Uncertain

0.53

Sift

Benign

0.33

T;.;.

Sift4G

Benign

0.36

T;T;.

Polyphen

0.92

P;.;P

Vest4

0.60

MVP

0.63

MPC

0.29

ClinPred

0.016

GERP RS

5.3

Varity_R

0.16

gMVP

0.77

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