NM_000393.5:c.403-16T>A

Variant names:

• chr2-189097346-A-T
• rs117085226
• NM_000393.5:c.403-16T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000393.5(COL5A2):​c.403-16T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0102 in 1,613,276 control chromosomes in the GnomAD database, including 563 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (44 hom., cov: 32)
  • Exomes 𝑓: 0.0097 (519 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.417
• Publications: 2 publications found

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]

COL5A2 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Ehlers-Danlos syndrome, classic type, 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 2-189097346-A-T is Benign according to our data. Variant chr2-189097346-A-T is described in ClinVar as Benign. ClinVar VariationId is 136969.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.073 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.403-16T>A		intron_variant	Intron 5 of 53	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.265-16T>A		intron_variant	Intron 8 of 56		XP_011508875.1
COL5A2	XM_047443251.1	c.265-16T>A		intron_variant	Intron 10 of 58		XP_047299207.1
COL5A2	XM_047443252.1	c.265-16T>A		intron_variant	Intron 9 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.403-16T>A		intron_variant	Intron 5 of 53	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.-228-16T>A		intron_variant	Intron 5 of 46	5		ENSP00000482184.1
COL5A2	ENST00000649966.1	c.265-16T>A		intron_variant	Intron 5 of 10			ENSP00000496785.1

Frequencies

GnomAD3 genomes AF: 0.0147 AC: 2240 AN: 152144 Hom.: 41 Cov.: 32

Gnomad AFR AF: 0.0212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0308

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.0580

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.00914

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00107

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.0222 AC: 5590 AN: 251380 AF XY: 0.0239

Gnomad AFR exome AF: 0.0210

Gnomad AMR exome AF: 0.0371

Gnomad ASJ exome AF: 0.00308

Gnomad EAS exome AF: 0.0513

Gnomad FIN exome AF: 0.0101

Gnomad NFE exome AF: 0.00208

Gnomad OTH exome AF: 0.0168

GnomAD4 exome AF: 0.00970 AC: 14167 AN: 1461014 Hom.: 519 Cov.: 30 AF XY: 0.0116 AC XY: 8439 AN XY: 726868

African (AFR) AF: 0.0228 AC: 764 AN: 33454

American (AMR) AF: 0.0382 AC: 1708 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00287 AC: 75 AN: 26128

East Asian (EAS) AF: 0.0693 AC: 2749 AN: 39676

South Asian (SAS) AF: 0.0784 AC: 6760 AN: 86236

European-Finnish (FIN) AF: 0.00961 AC: 513 AN: 53386

Middle Eastern (MID) AF: 0.00572 AC: 33 AN: 5766

European-Non Finnish (NFE) AF: 0.000685 AC: 761 AN: 1111276

Other (OTH) AF: 0.0133 AC: 804 AN: 60370

GnomAD4 genome AF: 0.0148 AC: 2251 AN: 152262 Hom.: 44 Cov.: 32 AF XY: 0.0163 AC XY: 1212 AN XY: 74446

African (AFR) AF: 0.0212 AC: 881 AN: 41546

American (AMR) AF: 0.0311 AC: 476 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.0581 AC: 300 AN: 5162

South Asian (SAS) AF: 0.0795 AC: 384 AN: 4828

European-Finnish (FIN) AF: 0.00914 AC: 97 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00107 AC: 73 AN: 68030

Other (OTH) AF: 0.0132 AC: 28 AN: 2114

Alfa AF: 0.00678 Hom.: 3

Bravo AF: 0.0157

Asia WGS AF: 0.0690 AC: 240 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

May 14, 2013

GeneDx

Significance: 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. -

not provided Benign:2

Mar 16, 2017

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: The COL5A2 c.403-16T>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant of interest has been observed in a large, broad control population, ExAC, in 2692/120714 control chromosomes (91 homozygotes) at a frequency of 0.0223006, which is approximately 3568 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000063), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. The variant of interest has not, to our knowledge, been reported in affected individuals via publications nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.9
DANN	Benign	0.89
PhyloP100		0.42
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs117085226; hg19: chr2-189962072;