2-189079109-TAA-TA

Variant names:

• chr2-189079109-TA-T
• rs542134887
• NM_000393.5:c.961-3delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):​c.961-3delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,541,394 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: COL5A2 NM_000393.5 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.23
• Publications: 0 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 2-189079109-TA-T is Benign according to our data. Variant chr2-189079109-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 285912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000252 (38/150630) while in subpopulation AFR AF = 0.000559 (23/41156). AF 95% confidence interval is 0.000381. There are 0 homozygotes in GnomAd4. There are 18 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.961-3delT		splice_region 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.961-3delT		splice_region intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.958-3delT		splice_region intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.961-3delT		splice_region intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.000252 AC: 38 AN: 150518 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000496 AC: 106 AN: 213888 AF XY: 0.000396

Gnomad AFR exome AF: 0.000776

Gnomad AMR exome AF: 0.000891

Gnomad ASJ exome AF: 0.00275

Gnomad EAS exome AF: 0.000869

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000242

Gnomad OTH exome AF: 0.000803

GnomAD4 exome AF: 0.000549 AC: 764 AN: 1390764 Hom.: 0 Cov.: 29 AF XY: 0.000491 AC XY: 340 AN XY: 692856

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

African (AFR) AF: 0.000766 AC: 24 AN: 31340

American (AMR) AF: 0.000835 AC: 35 AN: 41932

Ashkenazi Jewish (ASJ) AF: 0.00223 AC: 55 AN: 24644

East Asian (EAS) AF: 0.000320 AC: 12 AN: 37514

South Asian (SAS) AF: 0.000267 AC: 22 AN: 82294

European-Finnish (FIN) AF: 0.000174 AC: 9 AN: 51602

Middle Eastern (MID) AF: 0.000182 AC: 1 AN: 5484

European-Non Finnish (NFE) AF: 0.000533 AC: 564 AN: 1058736

Other (OTH) AF: 0.000734 AC: 42 AN: 57218

⚠️ 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: 0.000252 AC: 38 AN: 150630 Hom.: 0 Cov.: 32 AF XY: 0.000245 AC XY: 18 AN XY: 73592

African (AFR) AF: 0.000559 AC: 23 AN: 41156

American (AMR) AF: 0.000265 AC: 4 AN: 15102

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 7 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 5132

South Asian (SAS) AF: 0.00 AC: 0 AN: 4756

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10244

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000593 AC: 4 AN: 67510

Other (OTH) AF: 0.00 AC: 0 AN: 2082

Alfa AF: 0.00345 Hom.: 0

Bravo AF: 0.000325

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.2
Mutation Taster		=86/14	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: rs542134887; hg19: chr2-189943835; COSMIC: COSV66410028;