rs117917418

Variant names:

• chr2-189110461-A-C
• rs117917418
• NM_000393.5:c.98-12T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000393.5(COL5A2):​c.98-12T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0114 in 1,606,384 control chromosomes in the GnomAD database, including 717 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (61 hom., cov: 32)
  • Exomes 𝑓: 0.011 (656 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Scores: Splicing: ADA: 0.0002545
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.681
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 2-189110461-A-C is Benign according to our data. Variant chr2-189110461-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0682 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.98-12T>G		intron	N/A	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.98-12T>G		intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.98-15T>G		intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.98-12T>G		intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1960 AN: 152194 Hom.: 61 Cov.: 32

Gnomad AFR AF: 0.00347

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0716

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.0354

Gnomad SAS AF: 0.00726

Gnomad FIN AF: 0.000847

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00660

Gnomad OTH AF: 0.0191

GnomAD2 exomes AF: 0.0284 AC: 7086 AN: 249584 AF XY: 0.0233

Gnomad AFR exome AF: 0.00289

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.000896

Gnomad EAS exome AF: 0.0304

Gnomad FIN exome AF: 0.00111

Gnomad NFE exome AF: 0.00726

Gnomad OTH exome AF: 0.0234

GnomAD4 exome AF: 0.0113 AC: 16360 AN: 1454072 Hom.: 656 Cov.: 29 AF XY: 0.0106 AC XY: 7666 AN XY: 724086

African (AFR) AF: 0.00201 AC: 67 AN: 33332

American (AMR) AF: 0.144 AC: 6448 AN: 44680

Ashkenazi Jewish (ASJ) AF: 0.000882 AC: 23 AN: 26084

East Asian (EAS) AF: 0.0619 AC: 2453 AN: 39640

South Asian (SAS) AF: 0.00723 AC: 622 AN: 86076

European-Finnish (FIN) AF: 0.00137 AC: 73 AN: 53358

Middle Eastern (MID) AF: 0.0165 AC: 95 AN: 5756

European-Non Finnish (NFE) AF: 0.00542 AC: 5989 AN: 1105000

Other (OTH) AF: 0.00981 AC: 590 AN: 60146

GnomAD4 genome AF: 0.0129 AC: 1963 AN: 152312 Hom.: 61 Cov.: 32 AF XY: 0.0137 AC XY: 1017 AN XY: 74488

African (AFR) AF: 0.00346 AC: 144 AN: 41580

American (AMR) AF: 0.0717 AC: 1097 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3472

East Asian (EAS) AF: 0.0355 AC: 184 AN: 5182

South Asian (SAS) AF: 0.00726 AC: 35 AN: 4820

European-Finnish (FIN) AF: 0.000847 AC: 9 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00660 AC: 449 AN: 68020

Other (OTH) AF: 0.0189 AC: 40 AN: 2116

Alfa AF: 0.0105 Hom.: 5

Bravo AF: 0.0198

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 2 (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
BayesDel_noAF	Benign	-0.68
CADD	Benign	13
DANN	Benign	0.85
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00025
dbscSNV1_RF	Benign	0.092
SpliceAI score (max)		0.030		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: rs117917418; hg19: chr2-189975187; COSMIC: COSV66410056;