rs6414122

Variant names:

• chr2-189060822-T-A
• rs6414122
• NM_000393.5:c.2032-39A>T

Your query was ambiguous. Multiple possible variants found:

• chr2-189060822-T-A
• chr2-189060822-T-C
• chr2-189060822-T-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.2032-39A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.973 in 1,548,112 control chromosomes in the GnomAD database, including 734,089 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.96 (69898 hom., cov: 31)
  • Exomes 𝑓: 0.98 (664191 hom.)
• Consequence: COL5A2 NM_000393.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.523
• Publications: 6 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 2-189060822-T-A is Benign according to our data. Variant chr2-189060822-T-A is described in ClinVar as Benign. ClinVar VariationId is 255997.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.976 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A2	NM_000393.5	c.2032-39A>T		intron_variant	Intron 30 of 53	ENST00000374866.9	NP_000384.2
COL5A2	XM_011510573.4	c.1894-39A>T		intron_variant	Intron 33 of 56		XP_011508875.1
COL5A2	XM_047443251.1	c.1894-39A>T		intron_variant	Intron 35 of 58		XP_047299207.1
COL5A2	XM_047443252.1	c.1894-39A>T		intron_variant	Intron 34 of 57		XP_047299208.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A2	ENST00000374866.9	c.2032-39A>T		intron_variant	Intron 30 of 53	1	NM_000393.5	ENSP00000364000.3
COL5A2	ENST00000618828.1	c.871-39A>T		intron_variant	Intron 23 of 46	5		ENSP00000482184.1
COL5A2	ENST00000470524.2	n.138-39A>T		intron_variant	Intron 3 of 7	5

Frequencies

GnomAD3 genomes AF: 0.958 AC: 145690 AN: 152154 Hom.: 69851 Cov.: 31

Gnomad AFR AF: 0.917

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.916

Gnomad ASJ AF: 0.975

Gnomad EAS AF: 0.964

Gnomad SAS AF: 0.975

Gnomad FIN AF: 0.999

Gnomad MID AF: 0.978

Gnomad NFE AF: 0.982

Gnomad OTH AF: 0.946

GnomAD2 exomes AF: 0.957 AC: 238822 AN: 249640 AF XY: 0.962

Gnomad AFR exome AF: 0.919

Gnomad AMR exome AF: 0.840

Gnomad ASJ exome AF: 0.972

Gnomad EAS exome AF: 0.970

Gnomad FIN exome AF: 0.998

Gnomad NFE exome AF: 0.982

Gnomad OTH exome AF: 0.961

GnomAD4 exome AF: 0.975 AC: 1361062 AN: 1395840 Hom.: 664191 Cov.: 22 AF XY: 0.976 AC XY: 681781 AN XY: 698704

African (AFR) AF: 0.917 AC: 29477 AN: 32152

American (AMR) AF: 0.847 AC: 37718 AN: 44554

Ashkenazi Jewish (ASJ) AF: 0.972 AC: 24987 AN: 25700

East Asian (EAS) AF: 0.938 AC: 36877 AN: 39314

South Asian (SAS) AF: 0.973 AC: 82498 AN: 84786

European-Finnish (FIN) AF: 0.998 AC: 53167 AN: 53278

Middle Eastern (MID) AF: 0.964 AC: 5441 AN: 5642

European-Non Finnish (NFE) AF: 0.983 AC: 1034483 AN: 1052300

Other (OTH) AF: 0.971 AC: 56414 AN: 58114

GnomAD4 genome AF: 0.957 AC: 145794 AN: 152272 Hom.: 69898 Cov.: 31 AF XY: 0.958 AC XY: 71332 AN XY: 74456

African (AFR) AF: 0.917 AC: 38102 AN: 41542

American (AMR) AF: 0.916 AC: 14011 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.975 AC: 3383 AN: 3470

East Asian (EAS) AF: 0.964 AC: 4991 AN: 5178

South Asian (SAS) AF: 0.975 AC: 4705 AN: 4826

European-Finnish (FIN) AF: 0.999 AC: 10600 AN: 10612

Middle Eastern (MID) AF: 0.980 AC: 288 AN: 294

European-Non Finnish (NFE) AF: 0.982 AC: 66801 AN: 68026

Other (OTH) AF: 0.947 AC: 2001 AN: 2114

Alfa AF: 0.968 Hom.: 13090

Bravo AF: 0.947

Asia WGS AF: 0.970 AC: 3375 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

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. -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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	-0.89
CADD	Benign	1.5
DANN	Benign	0.71
PhyloP100		0.52
BranchPoint Hunter		1.0
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: rs6414122; hg19: chr2-189925548;