NM_000393.5:c.5T>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000393.5(COL5A2):c.5T>C(p.Met2Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000281 in 1,603,242 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000030 ( 0 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:2

Conservation

PhyloP100: 5.72

Publications

3 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 -9 ACMG points.

BP6

Variant 2-189179600-A-G is Benign according to our data. Variant chr2-189179600-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213138.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0000303 (44/1451056) while in subpopulation NFE AF = 0.0000344 (38/1105312). AF 95% confidence interval is 0.0000255. There are 0 homozygotes in GnomAdExome4. There are 25 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.5T>C	p.Met2Thr	missense_variant	Exon 1 of 54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.-42+45548T>C		intron_variant	Intron 4 of 56		XP_011508875.1
COL5A2	XM_047443251.1 link	c.-42+45548T>C		intron_variant	Intron 6 of 58		XP_047299207.1
COL5A2	XM_047443252.1 link	c.-42+45548T>C		intron_variant	Intron 5 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL5A2	ENST00000374866.9 link	c.5T>C	p.Met2Thr	missense_variant	Exon 1 of 54	1	NM_000393.5	ENSP00000364000.3	P05997
COL5A2	ENST00000618828.1 link	c.-626T>C		5_prime_UTR_variant	Exon 1 of 47	5		ENSP00000482184.1	A0A087WYX9
COL5A2	ENST00000649966.1 link	c.-42+45548T>C		intron_variant	Intron 1 of 10			ENSP00000496785.1	A0A3B3IRH9

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000469

AC:

AN:

234428

AF XY:

0.0000713

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000871

Gnomad OTH exome

AF:

0.000172

GnomAD4 exome

AF:

0.0000303

AC:

AN:

1451056

Hom.:

Cov.:

AF XY:

0.0000347

AC XY:

AN XY:

720802

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33346

American (AMR)

AF:

0.00

AC:

AN:

43914

Ashkenazi Jewish (ASJ)

AF:

0.0000390

AC:

AN:

25650

East Asian (EAS)

AF:

0.00

AC:

AN:

39634

South Asian (SAS)

AF:

0.00

AC:

AN:

84728

European-Finnish (FIN)

AF:

0.0000569

AC:

AN:

52752

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

0.0000344

AC:

AN:

1105312

Other (OTH)

AF:

0.0000334

AC:

AN:

59964

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

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:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41454

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

68022

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.725

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000675

Hom.:

Bravo

AF:

0.0000151

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:6Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:3

Jun 11, 2020

Mayo Clinic Laboratories, Mayo Clinic

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Apr 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

COL5A2: PP2, PP3 -

Jun 20, 2024

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Reported in a patient with classic Ehlers-Danlos syndrome who also harbored the p.(P659L) variant in COL5A2 (PMID: 33161638); In silico analysis indicates that this missense variant does not alter protein structure/function; Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); This variant is associated with the following publications: (PMID: 22696272, 33161638) -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Jan 07, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.M2T variant (also known as c.5T>C), located in coding exon 1 of the COL5A2 gene, results from a T to C substitution at nucleotide position 5. The methionine at codon 2 is replaced by threonine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

COL5A2-related disorder

Uncertain:1

Aug 12, 2024

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

The COL5A2 c.5T>C variant is predicted to result in the amino acid substitution p.Met2Thr. To our knowledge, this variant was reported as a variant of uncertain significance in a cohort of patients with bleeding disorders (Leinøe et al. 2017. PubMed ID: 28748566). This variant is reported in 0.011% of alleles in individuals of Ashkenazi Jewish descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-190044326-A-G). Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Ehlers-Danlos syndrome, classic type, 2

Uncertain:1

Nov 22, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The COL5A2 c.5T>C; p.Met2Thr variant (rs762874073; ClinVar ID: 213138) is reported in the literature in an individual with a bleeding disorder (Fager Ferrari 2021), although to our knowledge it has not been reported in association with an aortopathy disorder. This variant is found in the non-Finnish European population with an allele frequency of 0.009% (9/103,342 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.601). Due to limited information, the clinical significance of this variant is uncertain at this time. References: Fager Ferrari M et al. Collagen remodelling and plasma ascorbic acid levels in patients suspected of inherited bleeding disorders harbouring germline variants in collagen-related genes. Haemophilia. 2021 Jan;27(1):e69-e77. PMID: 33161638. -

not specified

Benign:1

Aug 05, 2024

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

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: COL5A2 c.5T>C (p.Met2Thr) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4.7e-05 in 234428 control chromosomes. The observed variant frequency is approximately 7.51 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A2 causing Ehlers-Danlos Syndrome phenotype (6.3e-06). To our knowledge, no occurrence of c.5T>C in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 213138). Based on the evidence outlined above, the variant was classified as likely benign. -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Feb 04, 2025

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

0.20

BayesDel_addAF

Pathogenic

0.17

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.27

T;T

Eigen

Uncertain

0.22

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.36

.;T

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.70

D;D

MetaSVM

Uncertain

0.081

MutationAssessor

Benign

0.0

N;N

PhyloP100

5.7

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-1.4

N;.

REVEL

Uncertain

0.60

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

0.72

P;P

Vest4

0.78

MutPred

0.47

Gain of glycosylation at M2 (P = 0.0099);Gain of glycosylation at M2 (P = 0.0099);

MVP

0.96

MPC

0.37

ClinPred

0.26

GERP RS

4.8

PromoterAI

0.14

Neutral

(source)

Varity_R

0.85

gMVP

0.68

Mutation Taster

=66/34

polymorphism

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over