2-189053611-T-C

Variant names:

• chr2-189053611-T-C
• rs6750027
• NM_000393.5:c.2500-134A>G

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.2500-134A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.913 in 831,206 control chromosomes in the GnomAD database, including 348,731 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.87 (58702 hom., cov: 30)
  • Exomes 𝑓: 0.92 (290029 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.77
• Publications: 5 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=-0.9).
• BP6: Variant 2-189053611-T-C is Benign according to our data. Variant chr2-189053611-T-C is described in ClinVar as Benign. ClinVar VariationId is 672286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.948 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2500-134A>G		intron_variant	Intron 37 of 53	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.2362-134A>G		intron_variant	Intron 40 of 56		XP_011508875.1
COL5A2	XM_047443251.1	c.2362-134A>G		intron_variant	Intron 42 of 58		XP_047299207.1
COL5A2	XM_047443252.1	c.2362-134A>G		intron_variant	Intron 41 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2500-134A>G		intron_variant	Intron 37 of 53	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.1339-134A>G		intron_variant	Intron 30 of 46	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.874 AC: 132725 AN: 151896 Hom.: 58678 Cov.: 30

Gnomad AFR AF: 0.739

Gnomad AMI AF: 0.968

Gnomad AMR AF: 0.824

Gnomad ASJ AF: 0.951

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.847

Gnomad FIN AF: 0.960

Gnomad MID AF: 0.889

Gnomad NFE AF: 0.954

Gnomad OTH AF: 0.877

GnomAD4 exome AF: 0.921 AC: 625853 AN: 679190 Hom.: 290029 AF XY: 0.920 AC XY: 329901 AN XY: 358570

African (AFR) AF: 0.733 AC: 12109 AN: 16524

American (AMR) AF: 0.766 AC: 21711 AN: 28358

Ashkenazi Jewish (ASJ) AF: 0.954 AC: 18332 AN: 19212

East Asian (EAS) AF: 0.778 AC: 25221 AN: 32436

South Asian (SAS) AF: 0.849 AC: 50236 AN: 59138

European-Finnish (FIN) AF: 0.957 AC: 45742 AN: 47784

Middle Eastern (MID) AF: 0.894 AC: 2774 AN: 3104

European-Non Finnish (NFE) AF: 0.955 AC: 418956 AN: 438798

Other (OTH) AF: 0.909 AC: 30772 AN: 33836

GnomAD4 genome AF: 0.874 AC: 132799 AN: 152016 Hom.: 58702 Cov.: 30 AF XY: 0.873 AC XY: 64880 AN XY: 74320

African (AFR) AF: 0.739 AC: 30606 AN: 41402

American (AMR) AF: 0.824 AC: 12577 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.951 AC: 3302 AN: 3472

East Asian (EAS) AF: 0.814 AC: 4202 AN: 5162

South Asian (SAS) AF: 0.847 AC: 4078 AN: 4814

European-Finnish (FIN) AF: 0.960 AC: 10151 AN: 10578

Middle Eastern (MID) AF: 0.884 AC: 260 AN: 294

European-Non Finnish (NFE) AF: 0.954 AC: 64898 AN: 68016

Other (OTH) AF: 0.876 AC: 1842 AN: 2102

Alfa AF: 0.897 Hom.: 7548

Bravo AF: 0.856

Asia WGS AF: 0.786 AC: 2732 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.017
DANN	Benign	0.48
PhyloP100		-2.8
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: rs6750027; hg19: chr2-189918337;