chr2-189068227-G-A
Variant summary
Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2BP4_StrongBP6_Very_StrongBS2
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. 17/23 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. T434K) has been classified as Uncertain significance.
Frequency
Consequence
NM_000393.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -15 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.1301C>T | p.Thr434Met | missense_variant, splice_region_variant | 20/54 | ENST00000374866.9 | |
COL5A2 | XM_011510573.4 | c.1163C>T | p.Thr388Met | missense_variant, splice_region_variant | 23/57 | ||
COL5A2 | XM_047443251.1 | c.1163C>T | p.Thr388Met | missense_variant, splice_region_variant | 25/59 | ||
COL5A2 | XM_047443252.1 | c.1163C>T | p.Thr388Met | missense_variant, splice_region_variant | 24/58 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.1301C>T | p.Thr434Met | missense_variant, splice_region_variant | 20/54 | 1 | NM_000393.5 | P1 | |
COL5A2 | ENST00000618828.1 | c.359-1794C>T | intron_variant | 5 |
Frequencies
GnomAD3 genomes AF: 0.00119 AC: 181AN: 152166Hom.: 1 Cov.: 32
GnomAD3 exomes AF: 0.00188 AC: 472AN: 251210Hom.: 8 AF XY: 0.00199 AC XY: 270AN XY: 135748
GnomAD4 exome AF: 0.00116 AC: 1692AN: 1461376Hom.: 21 Cov.: 31 AF XY: 0.00123 AC XY: 895AN XY: 727028
GnomAD4 genome AF: 0.00119 AC: 181AN: 152284Hom.: 1 Cov.: 32 AF XY: 0.00114 AC XY: 85AN XY: 74470
ClinVar
Submissions by phenotype
not provided Benign:6
Likely benign, no assertion criteria provided | clinical testing | Genome Diagnostics Laboratory, University Medical Center Utrecht | - | - - |
Benign, criteria provided, single submitter | clinical testing | GeneDx | Jun 05, 2019 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Benign, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Jan 01, 2024 | COL5A2: BS1, BS2 - |
Likely benign, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | May 31, 2017 | - - |
Benign, criteria provided, single submitter | clinical testing | ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Jul 11, 2017 | - - |
not specified Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Jul 21, 2023 | - - |
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 15, 2017 | 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 type 7A Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Ehlers-Danlos syndrome Benign:1
Benign, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Sep 28, 2021 | - - |
Ehlers-Danlos syndrome, classic type, 2 Benign:1
Benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jan 12, 2018 | 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. - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
Connective tissue disorder Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Center for Human Genetics, Inc, Center for Human Genetics, Inc | Nov 01, 2016 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at