rs768807471

Variant names:

• chr2-189179571-G-A
• rs768807471
• NM_000393.5:c.34C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_000393.5(COL5A2):​c.34C>T​(p.Leu12Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,457,620 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 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: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.10
• Publications: 0 publications found

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

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13605067).
• BP6: Variant 2-189179571-G-A is Benign according to our data. Variant chr2-189179571-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213139.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.34C>T	p.Leu12Phe	missense_variant	Exon 1 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.-42+45577C>T		intron_variant	Intron 4 of 56		XP_011508875.1
COL5A2	XM_047443251.1	c.-42+45577C>T		intron_variant	Intron 6 of 58		XP_047299207.1
COL5A2	XM_047443252.1	c.-42+45577C>T		intron_variant	Intron 5 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.34C>T	p.Leu12Phe	missense_variant	Exon 1 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.-597C>T		5_prime_UTR_variant	Exon 1 of 47	5		ENSP00000482184.1
COL5A2	ENST00000649966.1	c.-42+45577C>T		intron_variant	Intron 1 of 10			ENSP00000496785.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000410 AC: 1 AN: 244028 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457620 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 724720

African (AFR) AF: 0.00 AC: 0 AN: 33426

American (AMR) AF: 0.00 AC: 0 AN: 44346

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25828

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.00 AC: 0 AN: 85476

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53174

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109672

Other (OTH) AF: 0.00 AC: 0 AN: 60262

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jul 29, 2019

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.L12F variant (also known as c.34C>T), located in coding exon 1 of the COL5A2 gene, results from a C to T substitution at nucleotide position 34. The leucine at codon 12 is replaced by phenylalanine, an amino acid with highly similar properties. This amino acid position is not well conserved in available vertebrate species, and phenylalanine is the reference amino acid in other vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Dec 14, 2017

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

TAAD is a genetically heterogeneous disorder characterized by aortic dilatation, aneurysms, dissections and/or aneurysms of other major arteries. Approximately 4% of patients with autosomal dominant Ehlers-Danlos syndrome, classic type, have been reported to have a mutation in the COL5A2 gene (Malfait F et al., 2011).p.Leu12Phe (L12F) CTC>TTC: c.34 C>T in exon 1 of the COL5A2 gene (NM_000393.3)A variant of unknown significance has been identified in the COL5A2 gene. The L12F variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. The L12F variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is mostly conserved in mammals; however, F is present as the wild type in several species from Wallaby and beyond. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. No missense mutations in nearby residues have been reported in association with COL5A2-related disorder suggesting this region of the protein may be tolerant of change. Furthermore, the L12F variant does not affect a Glycine residue in a Gly-X-Y motif in the triple helical region of the COL5A2 gene, where the majority of missense mutations occur (Symoens et al., 2012). However, the L12F variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variantThis variant was found in TAADV2-1. -

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Jun 15, 2023

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	0.075
BayesDel_addAF	Benign	0.0046	T
BayesDel_noAF	Benign	-0.23
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.25
Eigen_PC	Benign	-0.038
FATHMM_MKL	Benign	0.53	D
LIST_S2	Benign	0.54	.;T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.14	T;T
MetaSVM	Benign	-0.52	T
MutationAssessor	Benign	0.0	N;N
PhyloP100		2.1
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-0.46	N;.
REVEL	Benign	0.28
Sift	Benign	0.47	T;.
Sift4G	Benign	0.12	T;.
Polyphen		0.0	B;B
Vest4		0.25
MutPred		0.48		Loss of sheet (P = 0.007);Loss of sheet (P = 0.007);
MVP		0.48
MPC		0.30
ClinPred		0.26	T
GERP RS		3.9
PromoterAI		-0.014	Neutral
Varity_R		0.060
gMVP		0.65
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs768807471; hg19: chr2-190044297;