chr2-189078578-G-A

Variant names:

• chr2-189078578-G-A
• rs73978832
• NM_000393.5:c.1006-9C>T

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.1006-9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0201 in 1,608,904 control chromosomes in the GnomAD database, including 415 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (24 hom., cov: 32)
  • Exomes 𝑓: 0.021 (391 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Scores: Splicing: ADA: 0.00002179
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.16
• Publications: 6 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=-0.88).
• BP6: Variant 2-189078578-G-A is Benign according to our data. Variant chr2-189078578-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136933.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 = 0.0154 (2348/152150) while in subpopulation NFE AF = 0.02 (1363/67996). AF 95% confidence interval is 0.0192. There are 24 homozygotes in GnomAd4. There are 1156 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2348 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.1006-9C>T		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.1006-9C>T		intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.1003-9C>T		intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.1006-9C>T		intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2351 AN: 152032 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00396

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.0139

Gnomad FIN AF: 0.0324

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0182

GnomAD2 exomes AF: 0.0171 AC: 4305 AN: 251310 AF XY: 0.0176

Gnomad AFR exome AF: 0.00412

Gnomad AMR exome AF: 0.00999

Gnomad ASJ exome AF: 0.0266

Gnomad EAS exome AF: 0.000326

Gnomad FIN exome AF: 0.0325

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0171

GnomAD4 exome AF: 0.0206 AC: 30032 AN: 1456754 Hom.: 391 Cov.: 30 AF XY: 0.0205 AC XY: 14840 AN XY: 724970

African (AFR) AF: 0.00327 AC: 109 AN: 33366

American (AMR) AF: 0.0113 AC: 503 AN: 44694

Ashkenazi Jewish (ASJ) AF: 0.0276 AC: 721 AN: 26080

East Asian (EAS) AF: 0.00388 AC: 154 AN: 39670

South Asian (SAS) AF: 0.0135 AC: 1165 AN: 86162

European-Finnish (FIN) AF: 0.0299 AC: 1595 AN: 53410

Middle Eastern (MID) AF: 0.0115 AC: 66 AN: 5750

European-Non Finnish (NFE) AF: 0.0222 AC: 24612 AN: 1107434

Other (OTH) AF: 0.0184 AC: 1107 AN: 60188

GnomAD4 genome AF: 0.0154 AC: 2348 AN: 152150 Hom.: 24 Cov.: 32 AF XY: 0.0155 AC XY: 1156 AN XY: 74370

African (AFR) AF: 0.00395 AC: 164 AN: 41512

American (AMR) AF: 0.0118 AC: 180 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0234 AC: 81 AN: 3468

East Asian (EAS) AF: 0.00271 AC: 14 AN: 5168

South Asian (SAS) AF: 0.0137 AC: 66 AN: 4816

European-Finnish (FIN) AF: 0.0324 AC: 343 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0200 AC: 1363 AN: 67996

Other (OTH) AF: 0.0180 AC: 38 AN: 2114

Alfa AF: 0.0183 Hom.: 8

Bravo AF: 0.0143

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	2	Ehlers-Danlos syndrome, classic type, 2 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	2.8
DANN	Benign	0.51
PhyloP100		-1.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000022
dbscSNV1_RF	Benign	0.0
Splicevardb		2.0
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: rs73978832; hg19: chr2-189943304; COSMIC: COSV104425976;