2-189039508-G-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000393.5(COL5A2):​c.3689C>G​(p.Thr1230Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00756 in 1,614,060 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. T1230S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0058 ( 5 hom., cov: 31)
Exomes 𝑓: 0.0077 ( 59 hom. )

Consequence

COL5A2
NM_000393.5 missense

Scores

8
11

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 4.66
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0091317).
BP6
Variant 2-189039508-G-C is Benign according to our data. Variant chr2-189039508-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 136952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189039508-G-C is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00578 (881/152300) while in subpopulation NFE AF= 0.00979 (666/68020). AF 95% confidence interval is 0.00917. There are 5 homozygotes in gnomad4. There are 400 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
BS2
High AC in GnomAd4 at 881 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL5A2NM_000393.5 linkc.3689C>G p.Thr1230Arg missense_variant Exon 51 of 54 ENST00000374866.9 NP_000384.2 P05997
COL5A2XM_011510573.4 linkc.3551C>G p.Thr1184Arg missense_variant Exon 54 of 57 XP_011508875.1
COL5A2XM_047443251.1 linkc.3551C>G p.Thr1184Arg missense_variant Exon 56 of 59 XP_047299207.1
COL5A2XM_047443252.1 linkc.3551C>G p.Thr1184Arg missense_variant Exon 55 of 58 XP_047299208.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL5A2ENST00000374866.9 linkc.3689C>G p.Thr1230Arg missense_variant Exon 51 of 54 1 NM_000393.5 ENSP00000364000.3 P05997
COL5A2ENST00000618828.1 linkc.2528C>G p.Thr843Arg missense_variant Exon 44 of 47 5 ENSP00000482184.1 A0A087WYX9

Frequencies

GnomAD3 genomes
AF:
0.00579
AC:
881
AN:
152182
Hom.:
5
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00174
Gnomad AMI
AF:
0.00219
Gnomad AMR
AF:
0.00537
Gnomad ASJ
AF:
0.000576
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00186
Gnomad FIN
AF:
0.00367
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00979
Gnomad OTH
AF:
0.00431
GnomAD3 exomes
AF:
0.00487
AC:
1221
AN:
250610
Hom.:
2
AF XY:
0.00509
AC XY:
690
AN XY:
135574
show subpopulations
Gnomad AFR exome
AF:
0.00144
Gnomad AMR exome
AF:
0.00260
Gnomad ASJ exome
AF:
0.000894
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00180
Gnomad FIN exome
AF:
0.00379
Gnomad NFE exome
AF:
0.00825
Gnomad OTH exome
AF:
0.00441
GnomAD4 exome
AF:
0.00774
AC:
11318
AN:
1461760
Hom.:
59
Cov.:
32
AF XY:
0.00751
AC XY:
5463
AN XY:
727182
show subpopulations
Gnomad4 AFR exome
AF:
0.00119
Gnomad4 AMR exome
AF:
0.00304
Gnomad4 ASJ exome
AF:
0.00130
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00176
Gnomad4 FIN exome
AF:
0.00391
Gnomad4 NFE exome
AF:
0.00933
Gnomad4 OTH exome
AF:
0.00599
GnomAD4 genome
AF:
0.00578
AC:
881
AN:
152300
Hom.:
5
Cov.:
31
AF XY:
0.00537
AC XY:
400
AN XY:
74464
show subpopulations
Gnomad4 AFR
AF:
0.00173
Gnomad4 AMR
AF:
0.00536
Gnomad4 ASJ
AF:
0.000576
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00186
Gnomad4 FIN
AF:
0.00367
Gnomad4 NFE
AF:
0.00979
Gnomad4 OTH
AF:
0.00426
Alfa
AF:
0.00499
Hom.:
0
Bravo
AF:
0.00603
TwinsUK
AF:
0.0135
AC:
50
ALSPAC
AF:
0.0104
AC:
40
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00779
AC:
67
ExAC
AF:
0.00456
AC:
554
Asia WGS
AF:
0.000577
AC:
2
AN:
3478
EpiCase
AF:
0.00714
EpiControl
AF:
0.00705

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:13
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:4
Jul 21, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jan 23, 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. -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Jun 20, 2017
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 2 Benign:2
Jan 13, 2018
Illumina Laboratory Services, Illumina
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Nov 04, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Mar 01, 2025
CeGaT Center for Human Genetics Tuebingen
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

COL5A2: PP2, BS2 -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Familial thoracic aortic aneurysm and aortic dissection Benign:1
Apr 27, 2015
Ambry Genetics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome Benign:1
May 12, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome type 7A Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type Benign:1
Nov 01, 2016
Center for Human Genetics, Inc, Center for Human Genetics, Inc
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:1
Feb 02, 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
AlphaMissense
Uncertain
0.46
BayesDel_addAF
Benign
-0.19
T
BayesDel_noAF
Uncertain
-0.030
CADD
Benign
23
DANN
Benign
0.96
DEOGEN2
Benign
0.34
T;T;T
Eigen
Uncertain
0.26
Eigen_PC
Uncertain
0.36
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.76
.;T;T
M_CAP
Benign
0.045
D
MetaRNN
Benign
0.0091
T;T;T
MetaSVM
Uncertain
-0.16
T
MutationAssessor
Benign
1.2
L;.;L
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
-1.5
N;.;.
REVEL
Uncertain
0.53
Sift
Benign
0.33
T;.;.
Sift4G
Benign
0.36
T;T;.
Polyphen
0.92
P;.;P
Vest4
0.60
MVP
0.63
MPC
0.29
ClinPred
0.016
T
GERP RS
5.3
Varity_R
0.16
gMVP
0.77

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs62184175; hg19: chr2-189904234; COSMIC: COSV99058942; API