NM_000393.5:c.1081A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000393.5(COL5A2):c.1081A>C(p.Met361Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0252 in 1,605,532 control chromosomes in the GnomAD database, including 568 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. M361V) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.018 ( 33 hom., cov: 32)

Exomes 𝑓: 0.026 ( 535 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14

Conservation

PhyloP100: 4.45

Publications

10 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0057465136).

BP6

Variant 2-189075416-T-G is Benign according to our data. Variant chr2-189075416-T-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0184 (2803/152270) while in subpopulation NFE AF = 0.0286 (1948/67994). AF 95% confidence interval is 0.0276. There are 33 homozygotes in GnomAd4. There are 1279 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 2803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.1081A>C	p.Met361Leu	missense_variant	Exon 17 of 54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.943A>C	p.Met315Leu	missense_variant	Exon 20 of 57		XP_011508875.1
COL5A2	XM_047443251.1 link	c.943A>C	p.Met315Leu	missense_variant	Exon 22 of 59		XP_047299207.1
COL5A2	XM_047443252.1 link	c.943A>C	p.Met315Leu	missense_variant	Exon 21 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9 link	c.1081A>C	p.Met361Leu	missense_variant	Exon 17 of 54	1	NM_000393.5	ENSP00000364000.3		P05997
COL5A2	ENST00000618828.1 link	c.358+3664A>C		intron_variant	Intron 15 of 46	5		ENSP00000482184.1		A0A087WYX9

Frequencies

GnomAD3 genomes

AF:

0.0184

AC:

2805

AN:

152152

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00606

Gnomad AMI

AF:

0.0186

Gnomad AMR

AF:

0.0210

Gnomad ASJ

AF:

0.0236

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00725

Gnomad FIN

AF:

0.00819

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.0286

Gnomad OTH

AF:

0.0244

GnomAD2 exomes

AF:

0.0184

AC:

4629

AN:

251122

AF XY:

0.0192

show subpopulations

Gnomad AFR exome

AF:

0.00413

Gnomad AMR exome

AF:

0.0121

Gnomad ASJ exome

AF:

0.0217

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00804

Gnomad NFE exome

AF:

0.0289

Gnomad OTH exome

AF:

0.0242

GnomAD4 exome

AF:

0.0259

AC:

37645

AN:

1453262

Hom.:

535

Cov.:

AF XY:

0.0256

AC XY:

18523

AN XY:

723470

show subpopulations

African (AFR)

AF:

0.00487

AC:

162

AN:

33290

American (AMR)

AF:

0.0127

AC:

567

AN:

44672

Ashkenazi Jewish (ASJ)

AF:

0.0218

AC:

567

AN:

26024

East Asian (EAS)

AF:

0.0000506

AC:

AN:

39534

South Asian (SAS)

AF:

0.0102

AC:

877

AN:

85968

European-Finnish (FIN)

AF:

0.00883

AC:

471

AN:

53326

Middle Eastern (MID)

AF:

0.0383

AC:

220

AN:

5746

European-Non Finnish (NFE)

AF:

0.0301

AC:

33303

AN:

1104642

Other (OTH)

AF:

0.0246

AC:

1476

AN:

60060

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

1510

3019

4529

6038

7548

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1260

2520

3780

5040

6300

<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:

0.0184

AC:

2803

AN:

152270

Hom.:

Cov.:

AF XY:

0.0172

AC XY:

1279

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.00604

AC:

251

AN:

41566

American (AMR)

AF:

0.0210

AC:

321

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.0236

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5180

South Asian (SAS)

AF:

0.00746

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00819

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.0272

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0286

AC:

1948

AN:

67994

Other (OTH)

AF:

0.0242

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

142

285

427

570

712

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0251

Hom.:

189

Bravo

AF:

0.0188

TwinsUK

AF:

0.0262

AC:

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0281

AC:

242

ExAC

AF:

0.0183

AC:

2217

Asia WGS

AF:

0.00491

AC:

AN:

3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:6

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 25, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 20, 2015

Eurofins Ntd Llc (ga)

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Genome Diagnostics Laboratory, University Medical Center Utrecht

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 09, 2025

Molecular Diagnostic Laboratory for Inherited Cardiovascular Disease, Montreal Heart Institute

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, classic type, 2

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Nov 11, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:2

Mar 21, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The COL5A2 c.1081A>C (p.Met361Leu) variant causes a missense change involving the alteration of a conserved nucleotide. 3/3 in silico tools predict a benign outcome (SNPs&GO and MutationTaster not captured here due to low reliability index and p-value, respectively). This variant has been observed in a large, broad control population, ExAC, in 2216/120978 control chromosomes (38 homozygotes) at a frequency of 0.0183174, which is approximately 2931 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Feb 06, 2015

Ambry Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

May 21, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome type 7A

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Feb 03, 2025

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

0.069

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.28

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.16

T;T

Eigen

Benign

-0.35

Eigen_PC

Benign

-0.090

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.82

.;T

MetaRNN

Benign

0.0057

T;T

MetaSVM

Benign

-0.42

MutationAssessor

Benign

-0.50

N;N

PhyloP100

4.5

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.59

N;.

REVEL

Benign

0.27

Sift

Benign

0.80

T;.

Sift4G

Benign

0.82

T;.

Polyphen

0.0

B;B

Vest4

0.11

MutPred

0.39

Loss of MoRF binding (P = 0.1233);Loss of MoRF binding (P = 0.1233);

MPC

0.48

ClinPred

0.025

GERP RS

5.2

Varity_R

0.25

gMVP

0.57

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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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