chr2-189039477-A-G

Variant names:

• chr2-189039477-A-G
• rs10208525
• NM_000393.5:c.3720T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000393.5(COL5A2):​c.3720T>C​(p.Tyr1240Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 1,613,900 control chromosomes in the GnomAD database, including 9,098 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.096 (724 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8374 hom.)
• Consequence: COL5A2 NM_000393.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.574
• Publications: 12 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-189039477-A-G is Benign according to our data. Variant chr2-189039477-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136954.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.574 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.142 is higher than 0.05.

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.3720T>C	p.Tyr1240Tyr	synonymous	Exon 51 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.3720T>C	p.Tyr1240Tyr	synonymous	Exon 51 of 54	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.3717T>C	p.Tyr1239Tyr	synonymous	Exon 51 of 54	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.3612T>C	p.Tyr1204Tyr	synonymous	Exon 50 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.0957 AC: 14542 AN: 152028 Hom.: 724 Cov.: 32

Gnomad AFR AF: 0.0721

Gnomad AMI AF: 0.0625

Gnomad AMR AF: 0.0989

Gnomad ASJ AF: 0.172

Gnomad EAS AF: 0.104

Gnomad SAS AF: 0.152

Gnomad FIN AF: 0.0890

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.105 AC: 26350 AN: 251060 AF XY: 0.110

Gnomad AFR exome AF: 0.0718

Gnomad AMR exome AF: 0.0658

Gnomad ASJ exome AF: 0.169

Gnomad EAS exome AF: 0.105

Gnomad FIN exome AF: 0.0903

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.117

GnomAD4 exome AF: 0.103 AC: 150569 AN: 1461754 Hom.: 8374 Cov.: 32 AF XY: 0.106 AC XY: 76882 AN XY: 727178

African (AFR) AF: 0.0732 AC: 2452 AN: 33480

American (AMR) AF: 0.0714 AC: 3192 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.167 AC: 4375 AN: 26136

East Asian (EAS) AF: 0.121 AC: 4802 AN: 39686

South Asian (SAS) AF: 0.160 AC: 13788 AN: 86248

European-Finnish (FIN) AF: 0.0930 AC: 4967 AN: 53394

Middle Eastern (MID) AF: 0.173 AC: 994 AN: 5746

European-Non Finnish (NFE) AF: 0.0985 AC: 109501 AN: 1111956

Other (OTH) AF: 0.108 AC: 6498 AN: 60392

GnomAD4 genome AF: 0.0956 AC: 14546 AN: 152146 Hom.: 724 Cov.: 32 AF XY: 0.0969 AC XY: 7208 AN XY: 74376

African (AFR) AF: 0.0723 AC: 3003 AN: 41522

American (AMR) AF: 0.0988 AC: 1510 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.172 AC: 597 AN: 3468

East Asian (EAS) AF: 0.103 AC: 534 AN: 5164

South Asian (SAS) AF: 0.151 AC: 727 AN: 4810

European-Finnish (FIN) AF: 0.0890 AC: 942 AN: 10582

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6914 AN: 67992

Other (OTH) AF: 0.105 AC: 221 AN: 2112

Alfa AF: 0.105 Hom.: 1513

Bravo AF: 0.0938

Asia WGS AF: 0.123 AC: 426 AN: 3478

EpiCase AF: 0.115

EpiControl AF: 0.117

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Ehlers-Danlos syndrome, classic type, 2 (2)
-	-	2	not provided (2)
-	-	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
BayesDel_noAF	Benign	-0.60
CADD	Benign	0.055
DANN	Benign	0.19
PhyloP100		-0.57
Mutation Taster		=100/0	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: rs10208525; hg19: chr2-189904203; COSMIC: COSV66408953;