NM_000393.5:c.2770-15delT

Variant names:

• chr2-189051495-GA-G
• rs577038385
• NM_000393.5:c.2770-15delT

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.2770-15delT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000745 in 1,592,972 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00076 (1 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 1.05
• Publications: 1 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 2-189051495-GA-G is Benign according to our data. Variant chr2-189051495-GA-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 213081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000565 (86/152202) while in subpopulation NFE AF = 0.000765 (52/67988). AF 95% confidence interval is 0.000599. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 86 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.2770-15delT		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.2770-15delT		intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.2767-15delT		intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.2770-15delT		intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152084 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000765

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000501 AC: 114 AN: 227710 AF XY: 0.000412

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.000275

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00141

Gnomad NFE exome AF: 0.000665

Gnomad OTH exome AF: 0.000752

GnomAD4 exome AF: 0.000763 AC: 1100 AN: 1440770 Hom.: 1 Cov.: 30 AF XY: 0.000755 AC XY: 541 AN XY: 716200

African (AFR) AF: 0.000155 AC: 5 AN: 32244

American (AMR) AF: 0.000327 AC: 13 AN: 39728

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24706

East Asian (EAS) AF: 0.00 AC: 0 AN: 39376

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83088

European-Finnish (FIN) AF: 0.00152 AC: 80 AN: 52686

Middle Eastern (MID) AF: 0.000186 AC: 1 AN: 5382

European-Non Finnish (NFE) AF: 0.000876 AC: 967 AN: 1104262

Other (OTH) AF: 0.000557 AC: 33 AN: 59298

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152202 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74416

African (AFR) AF: 0.000217 AC: 9 AN: 41538

American (AMR) AF: 0.000327 AC: 5 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00189 AC: 20 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000765 AC: 52 AN: 67988

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000582 Hom.: 0

Bravo AF: 0.000450

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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 type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.0
Mutation Taster		=100/0	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: rs577038385; hg19: chr2-189916221;