rs779153546

Variant names:

• chr2-189098753-C-T
• rs779153546
• NM_000393.5:c.376G>A

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PP3_Moderate BP6 BS1 BS2

The NM_000393.5(COL5A2):​c.376G>A​(p.Gly126Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000242 in 1,612,822 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (1 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: 4.77

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.857
• BP6: Variant 2-189098753-C-T is Benign according to our data. Variant chr2-189098753-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 213140.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3}.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000591 (9/152180) while in subpopulation AMR AF= 0.000327 (5/15284). AF 95% confidence interval is 0.000129. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.376G>A	p.Gly126Ser	missense_variant	Exon 5 of 54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.238G>A	p.Gly80Ser	missense_variant	Exon 8 of 57		XP_011508875.1
COL5A2	XM_047443251.1	c.238G>A	p.Gly80Ser	missense_variant	Exon 10 of 59		XP_047299207.1
COL5A2	XM_047443252.1	c.238G>A	p.Gly80Ser	missense_variant	Exon 9 of 58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.376G>A	p.Gly126Ser	missense_variant	Exon 5 of 54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000649966.1	c.238G>A	p.Gly80Ser	missense_variant	Exon 5 of 11			ENSP00000496785.1
COL5A2	ENST00000618828.1	c.-255G>A		5_prime_UTR_variant	Exon 5 of 47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000517 AC: 13 AN: 251232 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135798

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.0000205 AC: 30 AN: 1460642 Hom.: 1 Cov.: 29 AF XY: 0.0000151 AC XY: 11 AN XY: 726664

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000630

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152180 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74342

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000327

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

Bravo AF: 0.0000718

ExAC AF: 0.0000165 AC: 2

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Jul 30, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Identified on molecular autopsy in case of early sudden unexplained death (SUD) (PMID: 31847883); Not located in the triple helical region, where the majority of pathogenic missense variants occur (PMID: 22696272; HGMD); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 22696272, 31847883) -

Oct 26, 2021

Mayo Clinic Laboratories, Mayo Clinic

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Aug 10, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.G126S variant (also known as c.376G>A), located in coding exon 5 of the COL5A2 gene, results from a G to A substitution at nucleotide position 376. The glycine at codon 126 is replaced by serine, an amino acid with similar properties. This alteration has been reported in a sudden unexplained death cohort; however, clinical details were limited and an additional alteration in another cardiac-related gene was identified (Salfati EL et al. Genome Med, 2019 12;11:83). 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. -

not specified Benign:1

Apr 02, 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.376G>A (p.Gly126Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 5.2e-05 in 251232 control chromosomes (gnomAD). The observed variant frequency is approximately 8-fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A2 causing Ehlers-Danlos Syndrome phenotype (6.3e-06), strongly suggesting that the variant is benign. c.376G>A has been reported in the literature in an individual who suffered a sudden unexplained death who was found to have Brugada syndrome following autopsy, without strong evidence for causality (Salfari_2019). This report does not provide unequivocal conclusions about association of the variant with Ehlers-Danlos Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publication has been ascertained in the context of this evaluation (PMID: 31847883). ClinVar contains an entry for this variant (Variation ID: 213140). Based on the evidence outlined above, the variant was classified as likely benign. -

COL5A2-related disorder Benign:1

Oct 08, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Dec 10, 2024

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	Uncertain	0.36
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.28	T;T;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.87	.;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.86	D;D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	3.8	H;H;.
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.3	N;.;.
REVEL	Pathogenic	0.75
Sift	Benign	0.079	T;.;.
Sift4G	Benign	0.68	T;.;.
Polyphen		1.0	D;D;.
Vest4		0.71
MutPred		0.77		Gain of glycosylation at G126 (P = 0.0135);Gain of glycosylation at G126 (P = 0.0135);.;
MVP		0.92
MPC		0.92
ClinPred		0.83	D
GERP RS		5.6
Varity_R		0.11
gMVP		0.76

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

Other links and lift over

dbSNP: rs779153546; hg19: chr2-189963479;