rs146175905
Variant summary
Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2BP4_ModerateBP6BS2
The ENST00000374866.9(COL5A2):c.2117C>T(p.Pro706Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000484 in 1,613,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P706P) has been classified as Likely benign.
Frequency
Consequence
ENST00000374866.9 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Likely_benign. Variant got -6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL5A2 | NM_000393.5 | c.2117C>T | p.Pro706Leu | missense_variant | 32/54 | ENST00000374866.9 | NP_000384.2 | |
COL5A2 | XM_011510573.4 | c.1979C>T | p.Pro660Leu | missense_variant | 35/57 | XP_011508875.1 | ||
COL5A2 | XM_047443251.1 | c.1979C>T | p.Pro660Leu | missense_variant | 37/59 | XP_047299207.1 | ||
COL5A2 | XM_047443252.1 | c.1979C>T | p.Pro660Leu | missense_variant | 36/58 | XP_047299208.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL5A2 | ENST00000374866.9 | c.2117C>T | p.Pro706Leu | missense_variant | 32/54 | 1 | NM_000393.5 | ENSP00000364000 | P1 | |
COL5A2 | ENST00000618828.1 | c.956C>T | p.Pro319Leu | missense_variant | 25/47 | 5 | ENSP00000482184 | |||
COL5A2 | ENST00000470524.2 | n.223C>T | non_coding_transcript_exon_variant | 5/8 | 5 |
Frequencies
GnomAD3 genomes AF: 0.000158 AC: 24AN: 151440Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.000103 AC: 26AN: 251230Hom.: 0 AF XY: 0.0000810 AC XY: 11AN XY: 135816
GnomAD4 exome AF: 0.0000369 AC: 54AN: 1461522Hom.: 0 Cov.: 31 AF XY: 0.0000371 AC XY: 27AN XY: 727072
GnomAD4 genome AF: 0.000158 AC: 24AN: 151546Hom.: 0 Cov.: 32 AF XY: 0.000203 AC XY: 15AN XY: 74044
ClinVar
Submissions by phenotype
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Feb 15, 2022 | Has been reported in an individual with congenital heart defects, who also harbored variants in several other genes (Jin et al., 2017); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 28166811, 28991257, 27535533) - |
Uncertain significance, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The COL5A2 p.Pro706Leu variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs146175905) and in ClinVar (classified as a VUS by Invitae and Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital). The variant was also identified in control databases in 28 of 282454 chromosomes at a frequency of 0.000099 (Genome Aggregation Database Feb 27, 2017) and was observed in the following populations: African in 14 of 24910 chromosomes (freq: 0.000562), Other in 1 of 7210 chromosomes (freq: 0.000139), South Asian in 4 of 30594 chromosomes (freq: 0.000131), Latino in 4 of 35382 chromosomes (freq: 0.000113) and European (non-Finnish) in 5 of 129032 chromosomes (freq: 0.000039); it was not observed in the Ashkenazi Jewish, East Asian, and European (Finnish) populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Pro706 residue is conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) provide inconsistent predictions regarding the impact to the protein; this information is not very predictive of pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance. - |
Marfan syndrome Uncertain:1
Uncertain significance, no assertion criteria provided | clinical testing | Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital | Dec 30, 2016 | - - |
Familial thoracic aortic aneurysm and aortic dissection Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Nov 20, 2019 | The p.P706L variant (also known as c.2117C>T), located in coding exon 32 of the COL5A2 gene, results from a C to T substitution at nucleotide position 2117. The proline at codon 706 is replaced by leucine, an amino acid with similar properties. This alteration was detected in an individual with unspecified conotruncal defects who also carried the COL5A2 p.R1070H alteration (Jin SC et al. Nat. Genet., 2017 Nov;49:1593-1601). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. - |
Ehlers-Danlos syndrome, classic type, 1 Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 26, 2023 | - - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at