chr2-189053032-T-C

Variant names:

• chr2-189053032-T-C
• rs142429770
• NM_000393.5:c.2554-14A>G

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.2554-14A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00784 in 1,594,418 control chromosomes in the GnomAD database, including 67 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0066 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0080 (58 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.875
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 2-189053032-T-C is Benign according to our data. Variant chr2-189053032-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136945.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 = 0.00659 (1003/152302) while in subpopulation NFE AF = 0.00913 (621/68024). AF 95% confidence interval is 0.00853. There are 9 homozygotes in GnomAd4. There are 557 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1003 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.2554-14A>G		intron	N/A	NP_000384.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.2554-14A>G		intron	N/A	ENSP00000364000.3
	COL5A2	ENST00000618828.1	TSL:5	c.1393-14A>G		intron	N/A	ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.00660 AC: 1004 AN: 152184 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00171

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0240

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00913

Gnomad OTH AF: 0.00813

GnomAD2 exomes AF: 0.00686 AC: 1708 AN: 249120 AF XY: 0.00673

Gnomad AFR exome AF: 0.00169

Gnomad AMR exome AF: 0.00151

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0221

Gnomad NFE exome AF: 0.00923

Gnomad OTH exome AF: 0.00675

GnomAD4 exome AF: 0.00798 AC: 11502 AN: 1442116 Hom.: 58 Cov.: 27 AF XY: 0.00782 AC XY: 5622 AN XY: 718790

African (AFR) AF: 0.00106 AC: 35 AN: 33082

American (AMR) AF: 0.00159 AC: 71 AN: 44634

Ashkenazi Jewish (ASJ) AF: 0.00627 AC: 163 AN: 26010

East Asian (EAS) AF: 0.00 AC: 0 AN: 39578

South Asian (SAS) AF: 0.000152 AC: 13 AN: 85756

European-Finnish (FIN) AF: 0.0199 AC: 1063 AN: 53290

Middle Eastern (MID) AF: 0.000698 AC: 4 AN: 5734

European-Non Finnish (NFE) AF: 0.00898 AC: 9824 AN: 1094320

Other (OTH) AF: 0.00551 AC: 329 AN: 59712

GnomAD4 genome AF: 0.00659 AC: 1003 AN: 152302 Hom.: 9 Cov.: 32 AF XY: 0.00748 AC XY: 557 AN XY: 74480

African (AFR) AF: 0.00171 AC: 71 AN: 41562

American (AMR) AF: 0.00131 AC: 20 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00548 AC: 19 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.0240 AC: 255 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00913 AC: 621 AN: 68024

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00665 Hom.: 1

Bravo AF: 0.00469

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 2 (2)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type (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	-0.85
CADD	Benign	0.18
DANN	Benign	0.46
PhyloP100		-0.88
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: rs142429770; hg19: chr2-189917758;