chr2-189179600-A-G

Position:

chr2-189179600-A-G

Variant summary

Our verdict is Benign. Variant got -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

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 -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 id is 213138.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=5}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4_exome 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 gnomad4_exome. There are 25 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAdExome4 at 44 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5 link	c.5T>C	p.Met2Thr	missense_variant	1/54	ENST00000374866.9	NP_000384.2	P05997
COL5A2	XM_011510573.4 link	c.-42+45548T>C		intron_variant			XP_011508875.1
COL5A2	XM_047443251.1 link	c.-42+45548T>C		intron_variant			XP_047299207.1
COL5A2	XM_047443252.1 link	c.-42+45548T>C		intron_variant			XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL5A2	ENST00000374866.9 link	c.5T>C	p.Met2Thr	missense_variant	1/54	1	NM_000393.5	ENSP00000364000.3	P05997
COL5A2	ENST00000618828.1 link	c.-626T>C		5_prime_UTR_variant	1/47	5		ENSP00000482184.1	A0A087WYX9
COL5A2	ENST00000649966.1 link	c.-42+45548T>C		intron_variant				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

GnomAD3 exomes

AF:

0.0000469

AC:

AN:

234428

Hom.:

AF XY:

0.0000713

AC XY:

AN XY:

126228

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 SAS 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

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000390

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000569

Gnomad4 NFE exome

AF:

0.0000344

Gnomad4 OTH exome

AF:

0.0000334

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

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

Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jun 11, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 20, 2024	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) -

COL5A2-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 12, 2024

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. -

Familial thoracic aortic aneurysm and aortic dissection

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 30, 2019

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. -

Ehlers-Danlos syndrome, classic type, 2

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Nov 22, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

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

Aug 05, 2024

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 04, 2025

- -

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

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

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

Varity_R

0.85

gMVP

0.68

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