2-189032218-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):c.*1852T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00562 in 152,254 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (8 hom., cov: 33)
  • Failed GnomAD Quality Control
• Consequence: COL5A2 NM_000393.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.201

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 2-189032218-A-G is Benign according to our data. Variant chr2-189032218-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 333100.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00562 (856/152254) while in subpopulation SAS AF= 0.0333 (161/4830). AF 95% confidence interval is 0.0291. There are 8 homozygotes in gnomad4. There are 440 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 856 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A2	NM_000393.5	c.*1852T>C		3_prime_UTR_variant	54/54	ENST00000374866.9
COL5A2	XM_011510573.4	c.*1852T>C		3_prime_UTR_variant	57/57
COL5A2	XM_047443251.1	c.*1852T>C		3_prime_UTR_variant	59/59
COL5A2	XM_047443252.1	c.*1852T>C		3_prime_UTR_variant	58/58

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A2	ENST00000374866.9	c.*1852T>C		3_prime_UTR_variant	54/54	1	NM_000393.5	P1
COL5A2	ENST00000618828.1	c.*1852T>C		3_prime_UTR_variant	47/47	5

Frequencies

GnomAD3 genomes AF: 0.00563 AC: 856 AN: 152136 Hom.: 9 Cov.: 33

Gnomad AFR AF: 0.0126

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00269

Gnomad ASJ AF: 0.00779

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.0337

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00430

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

GnomAD4 genome AF: 0.00562 AC: 856 AN: 152254 Hom.: 8 Cov.: 33 AF XY: 0.00591 AC XY: 440 AN XY: 74458

Gnomad4 AFR AF: 0.0126

Gnomad4 AMR AF: 0.00262

Gnomad4 ASJ AF: 0.00779

Gnomad4 EAS AF: 0.00154

Gnomad4 SAS AF: 0.0333

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00112

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00433 Hom.: 1

Bravo AF: 0.00538

Asia WGS AF: 0.0570 AC: 197 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 21, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.8
Dann	Benign	0.80

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: rs116255986; hg19: chr2-189896944;