2-189032008-C-T

Position:

• chr2-189032008-C-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.*2062G>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 0.0125 in 152,142 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.012 (49 hom., cov: 32)
  • 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: -0.00600

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=-0.55).
• BP6: Variant 2-189032008-C-T is Benign according to our data. Variant chr2-189032008-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 333094.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0125 (1899/152142) while in subpopulation AFR AF= 0.0422 (1752/41520). AF 95% confidence interval is 0.0406. There are 49 homozygotes in gnomad4. There are 911 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 1899 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.*2062G>A		3_prime_UTR_variant	54/54	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.*2062G>A		3_prime_UTR_variant	57/57		XP_011508875.1
COL5A2	XM_047443251.1	c.*2062G>A		3_prime_UTR_variant	59/59		XP_047299207.1
COL5A2	XM_047443252.1	c.*2062G>A		3_prime_UTR_variant	58/58		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866	c.*2062G>A		3_prime_UTR_variant	54/54	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828	c.*2062G>A		3_prime_UTR_variant	47/47	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.0124 AC: 1884 AN: 152024 Hom.: 47 Cov.: 32

Gnomad AFR AF: 0.0419

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.0110

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: 0.0125 AC: 1899 AN: 152142 Hom.: 49 Cov.: 32 AF XY: 0.0122 AC XY: 911 AN XY: 74376

Gnomad4 AFR AF: 0.0422

Gnomad4 AMR AF: 0.00550

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000456

Gnomad4 OTH AF: 0.0109

Alfa AF: 0.00188 Hom.: 2

Bravo AF: 0.0141

Asia WGS AF: 0.00578 AC: 20 AN: 3472

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Ehlers-Danlos syndrome type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
CADD	Benign	4.6
DANN	Benign	0.58

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: rs77821675; hg19: chr2-189896734;