2-189071961-T-G

Variant names:

• chr2-189071961-T-G
• rs6434317
• NM_000393.5:c.1158+79A>C

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.1158+79A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.766 in 959,412 control chromosomes in the GnomAD database, including 285,112 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.71 (39524 hom., cov: 32)
  • Exomes 𝑓: 0.78 (245588 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.671
• Publications: 8 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=-0.81).
• BP6: Variant 2-189071961-T-G is Benign according to our data. Variant chr2-189071961-T-G is described in ClinVar as Benign. ClinVar VariationId is 672282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.802 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.1158+79A>C		intron_variant	Intron 18 of 53	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1020+79A>C		intron_variant	Intron 21 of 56		XP_011508875.1
COL5A2	XM_047443251.1	c.1020+79A>C		intron_variant	Intron 23 of 58		XP_047299207.1
COL5A2	XM_047443252.1	c.1020+79A>C		intron_variant	Intron 22 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.1158+79A>C		intron_variant	Intron 18 of 53	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.359-5528A>C		intron_variant	Intron 15 of 46	5		ENSP00000482184.1

Frequencies

GnomAD3 genomes AF: 0.712 AC: 108170 AN: 151860 Hom.: 39511 Cov.: 32

Gnomad AFR AF: 0.544

Gnomad AMI AF: 0.797

Gnomad AMR AF: 0.678

Gnomad ASJ AF: 0.721

Gnomad EAS AF: 0.716

Gnomad SAS AF: 0.661

Gnomad FIN AF: 0.821

Gnomad MID AF: 0.680

Gnomad NFE AF: 0.808

Gnomad OTH AF: 0.705

GnomAD4 exome AF: 0.776 AC: 626411 AN: 807434 Hom.: 245588 AF XY: 0.772 AC XY: 323947 AN XY: 419382

African (AFR) AF: 0.537 AC: 10606 AN: 19734

American (AMR) AF: 0.648 AC: 20744 AN: 32020

Ashkenazi Jewish (ASJ) AF: 0.725 AC: 15173 AN: 20938

East Asian (EAS) AF: 0.663 AC: 22427 AN: 33810

South Asian (SAS) AF: 0.663 AC: 41325 AN: 62310

European-Finnish (FIN) AF: 0.817 AC: 40022 AN: 49014

Middle Eastern (MID) AF: 0.642 AC: 2412 AN: 3756

European-Non Finnish (NFE) AF: 0.812 AC: 444736 AN: 547438

Other (OTH) AF: 0.754 AC: 28966 AN: 38414

GnomAD4 genome AF: 0.712 AC: 108221 AN: 151978 Hom.: 39524 Cov.: 32 AF XY: 0.710 AC XY: 52774 AN XY: 74286

African (AFR) AF: 0.543 AC: 22498 AN: 41436

American (AMR) AF: 0.679 AC: 10363 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.721 AC: 2502 AN: 3470

East Asian (EAS) AF: 0.716 AC: 3697 AN: 5166

South Asian (SAS) AF: 0.661 AC: 3185 AN: 4816

European-Finnish (FIN) AF: 0.821 AC: 8684 AN: 10572

Middle Eastern (MID) AF: 0.680 AC: 200 AN: 294

European-Non Finnish (NFE) AF: 0.808 AC: 54880 AN: 67934

Other (OTH) AF: 0.704 AC: 1485 AN: 2108

Alfa AF: 0.770 Hom.: 23099

Bravo AF: 0.694

Asia WGS AF: 0.637 AC: 2208 AN: 3462

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

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. -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.67
PhyloP100		-0.67
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: rs6434317; hg19: chr2-189936687;