2-189079109-TAA-TA

Variant names:

• chr2-189079109-TA-T
• rs542134887
• NM_000393.5:c.961-3delT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_000393.5(COL5A2):​c.961-3delT variant causes a splice region, 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 NM_000393.5 splice_region, 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 -16 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.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000252 (38/150630) while in subpopulation AFR AF= 0.000559 (23/41156). AF 95% confidence interval is 0.000381. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 38 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.961-3delT		splice_region_variant, intron_variant	Intron 14 of 53	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.823-3delT		splice_region_variant, intron_variant	Intron 17 of 56		XP_011508875.1
COL5A2	XM_047443251.1	c.823-3delT		splice_region_variant, intron_variant	Intron 19 of 58		XP_047299207.1
COL5A2	XM_047443252.1	c.823-3delT		splice_region_variant, intron_variant	Intron 18 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.961-3delT		splice_region_variant, intron_variant	Intron 14 of 53	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.331-3delT		splice_region_variant, intron_variant	Intron 14 of 46	5		ENSP00000482184.1

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

Sep 27, 2016

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 05, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1

Aug 18, 2021

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 type 7A Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 15, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome Benign:1

Dec 01, 2019

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;