2-189058904-ATTTT-ATT

Variant names:

• chr2-189058904-ATT-A
• rs5837121
• NM_000393.5:c.2086-13_2086-12delAA

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP6_Very_Strong

The NM_000393.5(COL5A2):​c.2086-13_2086-12delAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0336 in 1,055,026 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 0)
  • Exomes 𝑓: 0.039 (0 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.50
• Publications: 4 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 -8 ACMG points.

• BP6: Variant 2-189058904-ATT-A is Benign according to our data. Variant chr2-189058904-ATT-A is described in ClinVar as Benign. ClinVar VariationId is 517024.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.2086-13_2086-12delAA		intron	N/A	NP_000384.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.2086-13_2086-12delAA		intron	N/A	ENSP00000364000.3
	COL5A2	ENST00000618828.1	TSL:5	c.925-13_925-12delAA		intron	N/A	ENSP00000482184.1
	COL5A2	ENST00000470524.2	TSL:5	n.192-13_192-12delAA		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000891 AC: 133 AN: 149268 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00123

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000267

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000196

Gnomad SAS AF: 0.000633

Gnomad FIN AF: 0.00234

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000715

Gnomad OTH AF: 0.00147

GnomAD2 exomes AF: 0.0435 AC: 6785 AN: 155846 AF XY: 0.0459

Gnomad AFR exome AF: 0.0251

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0415

Gnomad EAS exome AF: 0.0394

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.0562

Gnomad OTH exome AF: 0.0495

GnomAD4 exome AF: 0.0390 AC: 35320 AN: 905650 Hom.: 0 AF XY: 0.0383 AC XY: 17290 AN XY: 450870

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0208 AC: 530 AN: 25472

American (AMR) AF: 0.0292 AC: 975 AN: 33354

Ashkenazi Jewish (ASJ) AF: 0.0419 AC: 646 AN: 15418

East Asian (EAS) AF: 0.0247 AC: 700 AN: 28336

South Asian (SAS) AF: 0.0380 AC: 2201 AN: 57936

European-Finnish (FIN) AF: 0.0272 AC: 962 AN: 35304

Middle Eastern (MID) AF: 0.0233 AC: 100 AN: 4300

European-Non Finnish (NFE) AF: 0.0416 AC: 27760 AN: 667576

Other (OTH) AF: 0.0381 AC: 1446 AN: 37954

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000890 AC: 133 AN: 149376 Hom.: 0 Cov.: 0 AF XY: 0.000865 AC XY: 63 AN XY: 72854

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00122 AC: 50 AN: 40890

American (AMR) AF: 0.000267 AC: 4 AN: 14998

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3424

East Asian (EAS) AF: 0.000196 AC: 1 AN: 5098

South Asian (SAS) AF: 0.000633 AC: 3 AN: 4738

European-Finnish (FIN) AF: 0.00234 AC: 23 AN: 9824

Middle Eastern (MID) AF: 0.00345 AC: 1 AN: 290

European-Non Finnish (NFE) AF: 0.000715 AC: 48 AN: 67148

Other (OTH) AF: 0.00146 AC: 3 AN: 2060

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.107 Hom.: 2945

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs5837121; hg19: chr2-189923630; COSMIC: COSV105930319;