2-189079109-TAA-TA

Position:

• chr2-189079109-TAA-TA

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The ENST00000374866.9(COL5A2):​c.961-3del variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00052 in 1,541,394 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00025 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00055 (0 hom.)
• Consequence: COL5A2 ENST00000374866.9 splice_region, splice_polypyrimidine_tract, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.23

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 -12 ACMG points.

• BP6: Variant 2-189079109-TA-T is Benign according to our data. Variant chr2-189079109-TA-T is described in ClinVar as [Likely_benign]. Clinvar id is 285912.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.961-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.823-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_011508875.1
COL5A2	XM_047443251.1	c.823-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047299207.1
COL5A2	XM_047443252.1	c.823-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant			XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.961-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000393.5	ENSP00000364000	P1
COL5A2	ENST00000618828.1	c.331-3del		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		ENSP00000482184

Frequencies

GnomAD3 genomes AF: 0.000252 AC: 38 AN: 150518 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000560

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000265

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000592

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000549 AC: 764 AN: 1390764 Hom.: 0 Cov.: 29 AF XY: 0.000491 AC XY: 340 AN XY: 692856

Gnomad4 AFR exome AF: 0.000766

Gnomad4 AMR exome AF: 0.000835

Gnomad4 ASJ exome AF: 0.00223

Gnomad4 EAS exome AF: 0.000320

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.000174

Gnomad4 NFE exome AF: 0.000533

Gnomad4 OTH exome AF: 0.000734

GnomAD4 genome AF: 0.000252 AC: 38 AN: 150630 Hom.: 0 Cov.: 32 AF XY: 0.000245 AC XY: 18 AN XY: 73592

Gnomad4 AFR AF: 0.000559

Gnomad4 AMR AF: 0.000265

Gnomad4 ASJ AF: 0.00203

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000593

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000325

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 27, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2016	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 18, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

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

Likely benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Feb 15, 2023

- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2019

- -

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, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs542134887; hg19: chr2-189943835;