2-189075416-T-G

Position:

• chr2-189075416-T-G

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/20 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 4.45

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 -19 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL5A2. . Gene score misZ 2.4395 (greater than the threshold 3.09). Trascript score misZ 3.3523 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, classic type, 2, Ehlers-Danlos syndrome, classic type.
• 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 [Likely_benign]. Clinvar id is 136935.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189075416-T-G is described in Lovd as [Benign]. Variant chr2-189075416-T-G is described in Lovd as [Likely_benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2803 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.1081A>C	p.Met361Leu	missense_variant	17/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.943A>C	p.Met315Leu	missense_variant	20/57
COL5A2	XM_047443251.1	c.943A>C	p.Met315Leu	missense_variant	22/59
COL5A2	XM_047443252.1	c.943A>C	p.Met315Leu	missense_variant	21/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.1081A>C	p.Met361Leu	missense_variant	17/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.358+3664A>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2805 AN: 152152 Hom.: 33 Cov.: 32

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

GnomAD3 exomes AF: 0.0184 AC: 4629 AN: 251122 Hom.: 83 AF XY: 0.0192 AC XY: 2612 AN XY: 135730

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 SAS exome AF: 0.0104

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.: 27 AF XY: 0.0256 AC XY: 18523 AN XY: 723470

Gnomad4 AFR exome AF: 0.00487

Gnomad4 AMR exome AF: 0.0127

Gnomad4 ASJ exome AF: 0.0218

Gnomad4 EAS exome AF: 0.0000506

Gnomad4 SAS exome AF: 0.0102

Gnomad4 FIN exome AF: 0.00883

Gnomad4 NFE exome AF: 0.0301

Gnomad4 OTH exome AF: 0.0246

GnomAD4 genome AF: 0.0184 AC: 2803 AN: 152270 Hom.: 33 Cov.: 32 AF XY: 0.0172 AC XY: 1279 AN XY: 74464

Gnomad4 AFR AF: 0.00604

Gnomad4 AMR AF: 0.0210

Gnomad4 ASJ AF: 0.0236

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00746

Gnomad4 FIN AF: 0.00819

Gnomad4 NFE AF: 0.0286

Gnomad4 OTH AF: 0.0242

Alfa AF: 0.0258 Hom.: 91

Bravo AF: 0.0188

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0257 AC: 99

ESP6500AA AF: 0.00567 AC: 25

ESP6500EA AF: 0.0281 AC: 242

ExAC AF: 0.0183 AC: 2217

Asia WGS AF: 0.00491 AC: 17 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 25, 2013	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. -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 20, 2015	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Ehlers-Danlos syndrome, classic type, 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 30, 2023	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2015

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 type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

May 21, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

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

Mar 21, 2017

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. -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	19
DANN	Benign	0.94
DEOGEN2	Benign	0.16	T;T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.090
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.82	.;T
MetaRNN	Benign	0.0057	T;T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	-0.50	N;N
MutationTaster	Benign	0.52	D
PrimateAI	Uncertain	0.60	T
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	T
GERP RS		5.2
Varity_R		0.25
gMVP		0.57

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: rs76148000; hg19: chr2-189940142;