2-189058904-ATTTT-ATTTTT

Variant names:

• chr2-189058904-A-AT
• rs5837121
• NM_000393.5:c.2086-12dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_000393.5(COL5A2):​c.2086-12dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (52 hom., cov: 0)
  • Exomes 𝑓: 0.012 (13 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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 -16 ACMG points.

• BP6: Variant 2-189058904-A-AT is Benign according to our data. Variant chr2-189058904-A-AT is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 377039.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.079 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.2086-12dupA		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.2086-12_2086-11insA		intron	N/A	ENSP00000364000.3
	COL5A2	ENST00000858728.1		c.2083-12_2083-11insA		intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.2086-12_2086-11insA		intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.0156 AC: 2339 AN: 149566 Hom.: 49 Cov.: 0

Gnomad AFR AF: 0.0234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0320

Gnomad ASJ AF: 0.00233

Gnomad EAS AF: 0.0575

Gnomad SAS AF: 0.0852

Gnomad FIN AF: 0.00948

Gnomad MID AF: 0.0160

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.0122

GnomAD2 exomes AF: 0.0316 AC: 4922 AN: 155846 AF XY: 0.0345

Gnomad AFR exome AF: 0.0299

Gnomad AMR exome AF: 0.0496

Gnomad ASJ exome AF: 0.00505

Gnomad EAS exome AF: 0.0661

Gnomad FIN exome AF: 0.0132

Gnomad NFE exome AF: 0.00320

Gnomad OTH exome AF: 0.0248

GnomAD4 exome AF: 0.0121 AC: 13216 AN: 1095856 Hom.: 13 Cov.: 0 AF XY: 0.0142 AC XY: 7790 AN XY: 549288

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

African (AFR) AF: 0.0300 AC: 835 AN: 27798

American (AMR) AF: 0.0424 AC: 1607 AN: 37924

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 75 AN: 20074

East Asian (EAS) AF: 0.0748 AC: 2468 AN: 32976

South Asian (SAS) AF: 0.0871 AC: 6041 AN: 69334

European-Finnish (FIN) AF: 0.0108 AC: 474 AN: 43894

Middle Eastern (MID) AF: 0.00699 AC: 34 AN: 4864

European-Non Finnish (NFE) AF: 0.00113 AC: 916 AN: 812986

Other (OTH) AF: 0.0167 AC: 766 AN: 46006

⚠️ 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: 0.0157 AC: 2352 AN: 149674 Hom.: 52 Cov.: 0 AF XY: 0.0172 AC XY: 1257 AN XY: 73028

African (AFR) AF: 0.0234 AC: 958 AN: 40916

American (AMR) AF: 0.0323 AC: 485 AN: 15016

Ashkenazi Jewish (ASJ) AF: 0.00233 AC: 8 AN: 3432

East Asian (EAS) AF: 0.0576 AC: 294 AN: 5102

South Asian (SAS) AF: 0.0859 AC: 407 AN: 4738

European-Finnish (FIN) AF: 0.00948 AC: 94 AN: 9912

Middle Eastern (MID) AF: 0.0138 AC: 4 AN: 290

European-Non Finnish (NFE) AF: 0.00110 AC: 74 AN: 67294

Other (OTH) AF: 0.0135 AC: 28 AN: 2068

Alfa AF: 0.00531 Hom.: 2945

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	not provided (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;