rs141571092

Variant names:

• chr2-189060790-C-T
• rs141571092
• NM_000393.5:c.2032-7G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):​c.2032-7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,612,026 control chromosomes in the GnomAD database, including 24 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0026 (15 hom., cov: 32)
  • Exomes 𝑓: 0.0029 (9 hom.)
• Consequence: COL5A2 NM_000393.5 splice_region, intron
• Scores: Splicing: ADA: 0.00009840
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -0.682
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.71).
• BP6: Variant 2-189060790-C-T is Benign according to our data. Variant chr2-189060790-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136943.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 = 0.00261 (397/152198) while in subpopulation NFE AF = 0.00319 (217/67984). AF 95% confidence interval is 0.00284. There are 15 homozygotes in GnomAd4. There are 171 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 397 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.2032-7G>A		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.2032-7G>A		splice_region intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.2029-7G>A		splice_region intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.2032-7G>A		splice_region intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.00261 AC: 397 AN: 152080 Hom.: 15 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.000590

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00123

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00319

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00167 AC: 419 AN: 250998 AF XY: 0.00158

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.000695

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00180

Gnomad NFE exome AF: 0.00290

Gnomad OTH exome AF: 0.00196

GnomAD4 exome AF: 0.00291 AC: 4250 AN: 1459828 Hom.: 9 Cov.: 29 AF XY: 0.00286 AC XY: 2075 AN XY: 726392

African (AFR) AF: 0.000329 AC: 11 AN: 33448

American (AMR) AF: 0.000582 AC: 26 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0000766 AC: 2 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86210

European-Finnish (FIN) AF: 0.00189 AC: 101 AN: 53376

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00355 AC: 3937 AN: 1110236

Other (OTH) AF: 0.00245 AC: 148 AN: 60324

GnomAD4 genome AF: 0.00261 AC: 397 AN: 152198 Hom.: 15 Cov.: 32 AF XY: 0.00230 AC XY: 171 AN XY: 74408

African (AFR) AF: 0.000554 AC: 23 AN: 41540

American (AMR) AF: 0.000589 AC: 9 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00123 AC: 13 AN: 10600

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00319 AC: 217 AN: 67984

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00297

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00311

EpiControl AF: 0.00314

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Ehlers-Danlos syndrome, classic type, 2 (2)
-	-	2	not provided (2)
-	-	1	Connective tissue disorder (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	-0.71
CADD	Benign	3.6
DANN	Benign	0.49
PhyloP100		-0.68
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000098
dbscSNV1_RF	Benign	0.0020
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: rs141571092; hg19: chr2-189925516;