rs369072636

Variant names:

• chr2-189050645-G-A
• rs369072636
• NM_000393.5:c.2963C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189050645-G-A
• chr2-189050645-G-T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM1 BP4_Moderate BP6 BS1 BS2

The NM_000393.5(COL5A2):​c.2963C>T​(p.Thr988Met) variant causes a missense change. The variant allele was found at a frequency of 0.0000663 in 1,552,428 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). Synonymous variant affecting the same amino acid position (i.e. T988T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: COL5A2 NM_000393.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 5.82
• Publications: 3 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 -9 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000393.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.20868).
• BP6: Variant 2-189050645-G-A is Benign according to our data. Variant chr2-189050645-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 213112.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00025 (38/152256) while in subpopulation AFR AF = 0.000578 (24/41556). AF 95% confidence interval is 0.000398. There are 0 homozygotes in GnomAd4. There are 17 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 38 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.2963C>T	p.Thr988Met	missense	Exon 43 of 54	NP_000384.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.2963C>T	p.Thr988Met	missense	Exon 43 of 54	ENSP00000364000.3
	COL5A2	ENST00000858728.1		c.2960C>T	p.Thr987Met	missense	Exon 43 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.2963C>T	p.Thr988Met	missense	Exon 43 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.000250 AC: 38 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000579

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000633 AC: 10 AN: 158048 AF XY: 0.0000601

Gnomad AFR exome AF: 0.000225

Gnomad AMR exome AF: 0.0000400

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000649

Gnomad NFE exome AF: 0.0000488

Gnomad OTH exome AF: 0.000225

GnomAD4 exome AF: 0.0000464 AC: 65 AN: 1400172 Hom.: 0 Cov.: 31 AF XY: 0.0000507 AC XY: 35 AN XY: 690716

African (AFR) AF: 0.000506 AC: 16 AN: 31624

American (AMR) AF: 0.000139 AC: 5 AN: 35998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35778

South Asian (SAS) AF: 0.000164 AC: 13 AN: 79264

European-Finnish (FIN) AF: 0.0000203 AC: 1 AN: 49268

Middle Eastern (MID) AF: 0.000177 AC: 1 AN: 5652

European-Non Finnish (NFE) AF: 0.0000222 AC: 24 AN: 1079366

Other (OTH) AF: 0.0000862 AC: 5 AN: 58038

GnomAD4 genome AF: 0.000250 AC: 38 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.000228 AC XY: 17 AN XY: 74436

African (AFR) AF: 0.000578 AC: 24 AN: 41556

American (AMR) AF: 0.000523 AC: 8 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5174

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.0000772 Hom.: 0

Bravo AF: 0.000238

ESP6500AA AF: 0.000701 AC: 3

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000514 AC: 5

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.012	T
BayesDel_noAF	Uncertain	0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.075	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.64	D
MutationAssessor	Benign	0.91	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-0.27	N
REVEL	Uncertain	0.47
Sift	Benign	0.076	T
Sift4G	Benign	0.17	T
Polyphen		1.0	D
Vest4		0.55
MVP		0.77
MPC		0.27
ClinPred		0.073	T
GERP RS		6.0
Varity_R		0.027
gMVP		0.18
Mutation Taster		=66/34	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs369072636; hg19: chr2-189915371; COSMIC: COSV66407638;