rs758412337

Positions:

• chr2-189042757-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2 BP4 BS2

The NM_000393.5(COL5A2):​c.3488A>G​(p.Gln1163Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,454,516 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.31

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 Likely_benign. Variant got -4 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=0.30958545).
• BS2: High AC in GnomAdExome4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.3488A>G	p.Gln1163Arg	missense_variant	49/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.3350A>G	p.Gln1117Arg	missense_variant	52/57		XP_011508875.1
COL5A2	XM_047443251.1	c.3350A>G	p.Gln1117Arg	missense_variant	54/59		XP_047299207.1
COL5A2	XM_047443252.1	c.3350A>G	p.Gln1117Arg	missense_variant	53/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.3488A>G	p.Gln1163Arg	missense_variant	49/54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.2327A>G	p.Gln776Arg	missense_variant	42/47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000666 AC: 16 AN: 240154 Hom.: 0 AF XY: 0.0000540 AC XY: 7 AN XY: 129550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000384

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000102

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1454516 Hom.: 0 Cov.: 31 AF XY: 0.0000124 AC XY: 9 AN XY: 722906

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000340

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000469

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000151

ExAC AF: 0.0000743 AC: 9

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 11, 2017

The p.Q1163R variant (also known as c.3488A>G), located in coding exon 49 of the COL5A2 gene, results from an A to G substitution at nucleotide position 3488. The glutamine at codon 1163 is replaced by arginine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. 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

Center for Genomics, Ann and Robert H. Lurie Children's Hospital of Chicago

Dec 15, 2022

This variant has not been reported in the literature but is present in the Genome Aggregation Database (Highest reported MAF: 0.04% [13/33820]; https://gnomad.broadinstitute.org/variant/2-189907483-T-C?dataset=gnomad_r2_1), and in ClinVar (Variation ID: 408279). Evolutionary conservation and computational prediction tools are unclear for this variant. In summary, data on this variant is insufficient for disease classification. Therefore, the clinical significance of this variant is uncertain. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 13, 2022

Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant does not alter protein structure/function -

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 19, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.024	T
BayesDel_noAF	Uncertain	0.11
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;T;D
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.81	.;T;T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.31	T;T;T
MetaSVM	Uncertain	0.56	D
MutationAssessor	Benign	0.95	L;.;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-2.3	N;.;.
REVEL	Uncertain	0.58
Sift	Uncertain	0.028	D;.;.
Sift4G	Benign	0.20	T;T;.
Polyphen		0.98	D;.;D
Vest4		0.27
MutPred		0.44		Gain of methylation at Q1163 (P = 0.0067);.;Gain of methylation at Q1163 (P = 0.0067);
MVP		0.91
MPC		0.28
ClinPred		0.22	T
GERP RS		5.8
Varity_R		0.20
gMVP		0.73

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: rs758412337; hg19: chr2-189907483;