2-189068038-G-A
Variant summary
Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1
The NM_000393.5(COL5A2):c.1378C>T(p.Pro460Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0454 in 1,613,706 control chromosomes in the GnomAD database, including 1,961 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).
Frequency
Consequence
NM_000393.5 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -20 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
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COL5A2 | NM_000393.5 | c.1378C>T | p.Pro460Ser | missense_variant | Exon 21 of 54 | ENST00000374866.9 | NP_000384.2 | |
COL5A2 | XM_011510573.4 | c.1240C>T | p.Pro414Ser | missense_variant | Exon 24 of 57 | XP_011508875.1 | ||
COL5A2 | XM_047443251.1 | c.1240C>T | p.Pro414Ser | missense_variant | Exon 26 of 59 | XP_047299207.1 | ||
COL5A2 | XM_047443252.1 | c.1240C>T | p.Pro414Ser | missense_variant | Exon 25 of 58 | XP_047299208.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.1378C>T | p.Pro460Ser | missense_variant | Exon 21 of 54 | 1 | NM_000393.5 | ENSP00000364000.3 | ||
COL5A2 | ENST00000618828.1 | c.359-1605C>T | intron_variant | Intron 15 of 46 | 5 | ENSP00000482184.1 |
Frequencies
GnomAD3 genomes AF: 0.0328 AC: 4990AN: 152096Hom.: 122 Cov.: 32
GnomAD3 exomes AF: 0.0317 AC: 7951AN: 251158Hom.: 169 AF XY: 0.0322 AC XY: 4368AN XY: 135726
GnomAD4 exome AF: 0.0467 AC: 68255AN: 1461492Hom.: 1839 Cov.: 32 AF XY: 0.0459 AC XY: 33363AN XY: 727080
GnomAD4 genome AF: 0.0328 AC: 4992AN: 152214Hom.: 122 Cov.: 32 AF XY: 0.0316 AC XY: 2351AN XY: 74398
ClinVar
Submissions by phenotype
not specified Benign:4
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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Ehlers-Danlos syndrome, classic type, 2 Benign:2
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. -
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not provided Benign:2
Variant summary: The COL5A2 c.1378C>T (p.Pro460Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant does not lie within a known functional domain (InterPro and UniProt) and 2/3 in silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in the large control database ExAC at a frequency of 0.0324101 (3927/121166 control chromosomes [80 homozygotes]), which is approximately 25928 times the estimated maximal expected allele frequency of a pathogenic COL5A2 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as benign. To our knowledge, the variant of interest has not been reported in affected individuals via publications, nor has it been evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as benign. -
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Familial thoracic aortic aneurysm and aortic dissection Benign:1
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
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Ehlers-Danlos syndrome type 7A Benign:1
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Ehlers-Danlos syndrome, classic type, 1 Benign:1
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Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at