chr2-189066418-A-G

Variant names:

• chr2-189066418-A-G
• rs35852101
• NM_000393.5:c.1535T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):​c.1535T>C​(p.Val512Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0211 in 1,614,122 control chromosomes in the GnomAD database, including 441 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 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. V512I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.018 (25 hom., cov: 33)
  • Exomes 𝑓: 0.021 (416 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 4.18
• Publications: 14 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011579573).
• BP6: Variant 2-189066418-A-G is Benign according to our data. Variant chr2-189066418-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136941.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0176 (2685/152316) while in subpopulation NFE AF = 0.0202 (1374/68028). AF 95% confidence interval is 0.0193. There are 25 homozygotes in GnomAd4. There are 1308 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2685 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.1535T>C	p.Val512Ala	missense	Exon 23 of 54	NP_000384.2	P05997

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.1535T>C	p.Val512Ala	missense	Exon 23 of 54	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.1532T>C	p.Val511Ala	missense	Exon 23 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.1535T>C	p.Val512Ala	missense	Exon 23 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.0177 AC: 2688 AN: 152198 Hom.: 25 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0137

Gnomad ASJ AF: 0.0242

Gnomad EAS AF: 0.00251

Gnomad SAS AF: 0.0141

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0202

Gnomad OTH AF: 0.0215

GnomAD2 exomes AF: 0.0182 AC: 4570 AN: 251398 AF XY: 0.0185

Gnomad AFR exome AF: 0.0109

Gnomad AMR exome AF: 0.0124

Gnomad ASJ exome AF: 0.0277

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0216

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0215 AC: 31380 AN: 1461806 Hom.: 416 Cov.: 31 AF XY: 0.0213 AC XY: 15461 AN XY: 727202

African (AFR) AF: 0.00866 AC: 290 AN: 33480

American (AMR) AF: 0.0139 AC: 623 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0292 AC: 762 AN: 26134

East Asian (EAS) AF: 0.00385 AC: 153 AN: 39694

South Asian (SAS) AF: 0.0136 AC: 1173 AN: 86258

European-Finnish (FIN) AF: 0.0299 AC: 1595 AN: 53420

Middle Eastern (MID) AF: 0.0139 AC: 80 AN: 5764

European-Non Finnish (NFE) AF: 0.0229 AC: 25495 AN: 1111944

Other (OTH) AF: 0.0200 AC: 1209 AN: 60392

GnomAD4 genome AF: 0.0176 AC: 2685 AN: 152316 Hom.: 25 Cov.: 33 AF XY: 0.0176 AC XY: 1308 AN XY: 74472

African (AFR) AF: 0.0108 AC: 450 AN: 41578

American (AMR) AF: 0.0136 AC: 208 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0242 AC: 84 AN: 3470

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5174

South Asian (SAS) AF: 0.0139 AC: 67 AN: 4824

European-Finnish (FIN) AF: 0.0324 AC: 344 AN: 10624

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0202 AC: 1374 AN: 68028

Other (OTH) AF: 0.0213 AC: 45 AN: 2116

Alfa AF: 0.0201 Hom.: 50

Bravo AF: 0.0170

TwinsUK AF: 0.0243 AC: 90

ALSPAC AF: 0.0285 AC: 110

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.0214 AC: 184

ExAC AF: 0.0182 AC: 2213

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0224

EpiControl AF: 0.0205

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 2 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	20
DANN	Benign	0.78
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.076
Eigen_PC	Benign	0.15
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.012	T
MetaSVM	Uncertain	0.15	D
MutationAssessor	Benign	0.41	N
PhyloP100		4.2
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.19	N
REVEL	Uncertain	0.44
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.46	P
Vest4		0.40
MPC		0.96
ClinPred		0.024	T
GERP RS		5.5
Varity_R		0.063
gMVP		0.43
Mutation Taster		=83/17	polymorphism (auto)

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: rs35852101; hg19: chr2-189931144;