rs145850743

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000393.5(COL5A2):c.1301C>T(p.Thr434Met) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,613,660 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T434A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0012 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0012 ( 21 hom. )

Consequence

COL5A2
NM_000393.5 missense, splice_region

Scores

Splicing: ADA: 0.002463

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15

Conservation

PhyloP100: 2.47

Publications

9 publications found

Variant links:

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

COL5A2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.01739955).

BP6

Variant 2-189068227-G-A is Benign according to our data. Variant chr2-189068227-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212979.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00119 (181/152284) while in subpopulation SAS AF = 0.00187 (9/4824). AF 95% confidence interval is 0.000973. There are 1 homozygotes in GnomAd4. There are 85 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 181 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000393.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A2	NM_000393.5	MANE Select	c.1301C>T	p.Thr434Met	missense splice_region	Exon 20 of 54	NP_000384.2	P05997

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL5A2	ENST00000374866.9	TSL:1 MANE Select	c.1301C>T	p.Thr434Met	missense splice_region	Exon 20 of 54	ENSP00000364000.3	P05997
COL5A2	ENST00000858728.1		c.1298C>T	p.Thr433Met	missense splice_region	Exon 20 of 54	ENSP00000528787.1
COL5A2	ENST00000858729.1		c.1301C>T	p.Thr434Met	missense splice_region	Exon 20 of 53	ENSP00000528788.1

Frequencies

GnomAD3 genomes

AF:

0.00119

AC:

181

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000217

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.0268

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000676

Gnomad OTH

AF:

0.00335

GnomAD2 exomes

AF:

0.00188

AC:

472

AN:

251210

AF XY:

0.00199

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000203

Gnomad ASJ exome

AF:

0.0273

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000323

Gnomad NFE exome

AF:

0.00102

Gnomad OTH exome

AF:

0.00277

GnomAD4 exome

AF:

0.00116

AC:

1692

AN:

1461376

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

895

AN XY:

727028

show subpopulations

African (AFR)

AF:

0.000239

AC:

AN:

33464

American (AMR)

AF:

0.000224

AC:

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0293

AC:

765

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00173

AC:

149

AN:

86246

European-Finnish (FIN)

AF:

0.000374

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000512

AC:

569

AN:

1111566

Other (OTH)

AF:

0.00263

AC:

159

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

102

205

307

410

512

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

128

160

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00119

AC:

181

AN:

152284

Hom.:

Cov.:

AF XY:

0.00114

AC XY:

AN XY:

74470

show subpopulations

African (AFR)

AF:

0.000217

AC:

AN:

41566

American (AMR)

AF:

0.000131

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00187

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000676

AC:

AN:

68018

Other (OTH)

AF:

0.00331

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.510

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00188

Hom.:

Bravo

AF:

0.00127

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00180

AC:

219

Asia WGS

AF:

0.000866

AC:

AN:

3478

EpiCase

AF:

0.00109

EpiControl

AF:

0.00154

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (7)

not specified (2)

Connective tissue disorder (1)

Ehlers-Danlos syndrome (1)

Ehlers-Danlos syndrome type 7A (1)

Ehlers-Danlos syndrome, classic type, 1 (1)

Ehlers-Danlos syndrome, classic type, 2 (1)

Familial thoracic aortic aneurysm and aortic dissection (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.088

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.21

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.35

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.82

M_CAP

Benign

0.059

MetaRNN

Benign

0.017

MetaSVM

Uncertain

-0.073

MutationAssessor

Benign

1.0

PhyloP100

2.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

REVEL

Benign

0.23

Sift

Benign

0.088

Sift4G

Benign

0.14

Polyphen

0.025

Vest4

0.31

MVP

0.65

MPC

0.94

ClinPred

0.038

GERP RS

4.3

Varity_R

0.035

gMVP

0.099

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0025

dbscSNV1_RF

Benign

0.20

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over