chr2-189032670-T-C

Variant names:

• chr2-189032670-T-C
• rs12886
• NM_000393.5:c.*1400A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000393.5(COL5A2):​c.*1400A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0155 in 152,350 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.016 (24 hom., cov: 32)
  • Exomes 𝑓: 0.026 (1 hom.)
• Consequence: COL5A2 NM_000393.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.698
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 2-189032670-T-C is Benign according to our data. Variant chr2-189032670-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 333107.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0155 (2358/152082) while in subpopulation NFE AF = 0.0201 (1365/67944). AF 95% confidence interval is 0.0192. There are 24 homozygotes in GnomAd4. There are 1169 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2358 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.*1400A>G		3_prime_UTR	Exon 54 of 54	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.*1400A>G		3_prime_UTR	Exon 54 of 54	ENSP00000364000.3	P05997
	COL5A2	ENST00000618828.1	TSL:5	c.*1400A>G		3_prime_UTR	Exon 47 of 47	ENSP00000482184.1	A0A087WYX9

Frequencies

GnomAD3 genomes AF: 0.0155 AC: 2361 AN: 151964 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.105

Gnomad AMR AF: 0.0119

Gnomad ASJ AF: 0.0234

Gnomad EAS AF: 0.00347

Gnomad SAS AF: 0.0147

Gnomad FIN AF: 0.0323

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0201

Gnomad OTH AF: 0.0177

GnomAD4 exome AF: 0.0261 AC: 7 AN: 268 Hom.: 1 Cov.: 0 AF XY: 0.0235 AC XY: 4 AN XY: 170

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.0267 AC: 7 AN: 262

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 2

Other (OTH) AF: 0.00 AC: 0 AN: 4

GnomAD4 genome AF: 0.0155 AC: 2358 AN: 152082 Hom.: 24 Cov.: 32 AF XY: 0.0157 AC XY: 1169 AN XY: 74376

African (AFR) AF: 0.00400 AC: 166 AN: 41512

American (AMR) AF: 0.0118 AC: 180 AN: 15248

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

East Asian (EAS) AF: 0.00348 AC: 18 AN: 5176

South Asian (SAS) AF: 0.0145 AC: 70 AN: 4824

European-Finnish (FIN) AF: 0.0323 AC: 342 AN: 10590

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

European-Non Finnish (NFE) AF: 0.0201 AC: 1365 AN: 67944

Other (OTH) AF: 0.0175 AC: 37 AN: 2114

Alfa AF: 0.0167 Hom.: 5

Bravo AF: 0.0143

Asia WGS AF: 0.00347 AC: 12 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	7.4
DANN	Benign	0.66
PhyloP100		0.70
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: rs12886; hg19: chr2-189897396;