rs367643805

Variant names:

• chr2-189043143-T-A
• rs367643805
• NM_000393.5:c.3471+8A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189043143-T-A
• chr2-189043143-T-C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000393.5(COL5A2):​c.3471+8A>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0011 in 1,604,170 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00057 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (1 hom.)
• Consequence: COL5A2 NM_000393.5 splice_region, intron
• Scores: Splicing: ADA: 0.0004781
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:12
• Conservation: PhyloP100: -0.268
• 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 2-189043143-T-A is Benign according to our data. Variant chr2-189043143-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 155778.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000572 (87/152164) while in subpopulation NFE AF = 0.00097 (66/68030). AF 95% confidence interval is 0.000782. There are 0 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 87 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.3471+8A>T		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.3471+8A>T		splice_region intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.3468+8A>T		splice_region intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.3363+8A>T		splice_region intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.000572 AC: 87 AN: 152164 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000970

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000532 AC: 132 AN: 248048 AF XY: 0.000627

Gnomad AFR exome AF: 0.000188

Gnomad AMR exome AF: 0.0000585

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.00110

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.00115 AC: 1672 AN: 1452006 Hom.: 1 Cov.: 29 AF XY: 0.00113 AC XY: 815 AN XY: 722714

African (AFR) AF: 0.000300 AC: 10 AN: 33290

American (AMR) AF: 0.0000900 AC: 4 AN: 44438

Ashkenazi Jewish (ASJ) AF: 0.0000385 AC: 1 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85620

European-Finnish (FIN) AF: 0.0000375 AC: 2 AN: 53318

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00146 AC: 1615 AN: 1103862

Other (OTH) AF: 0.000666 AC: 40 AN: 60088

GnomAD4 genome AF: 0.000572 AC: 87 AN: 152164 Hom.: 0 Cov.: 32 AF XY: 0.000565 AC XY: 42 AN XY: 74338

African (AFR) AF: 0.000290 AC: 12 AN: 41436

American (AMR) AF: 0.000262 AC: 4 AN: 15270

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.000970 AC: 66 AN: 68030

Other (OTH) AF: 0.00239 AC: 5 AN: 2090

Alfa AF: 0.000915 Hom.: 0

Bravo AF: 0.000699

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	not provided (4)
-	-	4	not specified (4)
-	-	2	Ehlers-Danlos syndrome, classic type, 2 (2)
-	-	1	Connective tissue disorder (1)
-	1	-	Disproportionate tall stature;C4707243:Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	1	-	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	3.1
DANN	Benign	0.64
PhyloP100		-0.27
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00048
dbscSNV1_RF	Benign	0.018
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: rs367643805; hg19: chr2-189907869;