2-189031939-A-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_000393.5(COL5A2):c.*2131T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0217 in 152,220 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.022 (40 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL5A2 NM_000393.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.978

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-189031939-A-T is Benign according to our data. Variant chr2-189031939-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 333093.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0217 (3298/152220) while in subpopulation AFR AF= 0.0258 (1073/41542). AF 95% confidence interval is 0.0245. There are 40 homozygotes in gnomad4. There are 1625 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 3301 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.*2131T>A		3_prime_UTR_variant	54/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.*2131T>A		3_prime_UTR_variant	57/57
COL5A2	XM_047443251.1	c.*2131T>A		3_prime_UTR_variant	59/59
COL5A2	XM_047443252.1	c.*2131T>A		3_prime_UTR_variant	58/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.*2131T>A		3_prime_UTR_variant	54/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.*2131T>A		3_prime_UTR_variant	47/47	5

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3301 AN: 152102 Hom.: 40 Cov.: 32

Gnomad AFR AF: 0.0260

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0205

Gnomad ASJ AF: 0.0309

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0130

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0222

Gnomad OTH AF: 0.0278

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 2

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0217 AC: 3298 AN: 152220 Hom.: 40 Cov.: 32 AF XY: 0.0218 AC XY: 1625 AN XY: 74454

Gnomad4 AFR AF: 0.0258

Gnomad4 AMR AF: 0.0204

Gnomad4 ASJ AF: 0.0309

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.0221

Gnomad4 OTH AF: 0.0275

Alfa AF: 0.0206 Hom.: 2

Bravo AF: 0.0219

Asia WGS AF: 0.0100 AC: 35 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome, classic type, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ehlers-Danlos syndrome type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	2.4
Dann	Benign	0.76

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

Publications

LitVar

Other links and lift over

dbSNP: rs113513554; hg19: chr2-189896665;