rs148220961

Variant names:

• chr2-189098775-G-A
• rs148220961
• NM_000393.5:c.370-16C>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.370-16C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00753 in 1,609,678 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0073 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (70 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.299
• Publications: 3 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 2-189098775-G-A is Benign according to our data. Variant chr2-189098775-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0073 (1112/152254) while in subpopulation AMR AF = 0.0172 (263/15286). AF 95% confidence interval is 0.0155. There are 8 homozygotes in GnomAd4. There are 523 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1112 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.370-16C>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.370-16C>T		intron	N/A	ENSP00000364000.3	P05997
	COL5A2	ENST00000858728.1		c.367-16C>T		intron	N/A	ENSP00000528787.1
	COL5A2	ENST00000858729.1		c.370-16C>T		intron	N/A	ENSP00000528788.1

Frequencies

GnomAD3 genomes AF: 0.00732 AC: 1114 AN: 152136 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00186

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0172

Gnomad ASJ AF: 0.0395

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000827

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00838

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00737 AC: 1848 AN: 250852 AF XY: 0.00719

Gnomad AFR exome AF: 0.00148

Gnomad AMR exome AF: 0.0113

Gnomad ASJ exome AF: 0.0346

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.000652

Gnomad NFE exome AF: 0.00839

Gnomad OTH exome AF: 0.0137

GnomAD4 exome AF: 0.00755 AC: 11003 AN: 1457424 Hom.: 70 Cov.: 28 AF XY: 0.00739 AC XY: 5363 AN XY: 725314

African (AFR) AF: 0.00147 AC: 49 AN: 33386

American (AMR) AF: 0.0124 AC: 552 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0342 AC: 892 AN: 26060

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39600

South Asian (SAS) AF: 0.00123 AC: 106 AN: 86142

European-Finnish (FIN) AF: 0.000677 AC: 36 AN: 53140

Middle Eastern (MID) AF: 0.0158 AC: 91 AN: 5758

European-Non Finnish (NFE) AF: 0.00792 AC: 8777 AN: 1108436

Other (OTH) AF: 0.00829 AC: 499 AN: 60226

GnomAD4 genome AF: 0.00730 AC: 1112 AN: 152254 Hom.: 8 Cov.: 33 AF XY: 0.00702 AC XY: 523 AN XY: 74452

African (AFR) AF: 0.00185 AC: 77 AN: 41542

American (AMR) AF: 0.0172 AC: 263 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0395 AC: 137 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4832

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10610

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

European-Non Finnish (NFE) AF: 0.00838 AC: 570 AN: 68006

Other (OTH) AF: 0.0104 AC: 22 AN: 2112

Alfa AF: 0.00980 Hom.: 2

Bravo AF: 0.00826

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Ehlers-Danlos syndrome, classic type (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
BayesDel_noAF	Benign	-0.71
CADD	Benign	3.7
DANN	Benign	0.78
PhyloP100		-0.30
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs148220961; hg19: chr2-189963501;