rs755159927
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PP2BP4
The NM_004370.6(COL12A1):c.7048G>T(p.Val2350Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0000441 in 1,611,626 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 Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000047 ( 0 hom. )
Consequence
COL12A1
NM_004370.6 missense
NM_004370.6 missense
Scores
12
7
Clinical Significance
Conservation
PhyloP100: 4.81
Genes affected
COL12A1 (HGNC:2188): (collagen type XII alpha 1 chain) This gene encodes the alpha chain of type XII collagen, a member of the FACIT (fibril-associated collagens with interrupted triple helices) collagen family. Type XII collagen is a homotrimer found in association with type I collagen, an association that is thought to modify the interactions between collagen I fibrils and the surrounding matrix. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 0 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL12A1. . Gene score misZ 2.106 (greater than the threshold 3.09). Trascript score misZ 3.5535 (greater than threshold 3.09). GenCC has associacion of gene with Bethlem myopathy, Bethlem myopathy 2, Ullrich congenital muscular dystrophy 2, Ullrich congenital muscular dystrophy.
BP4
Computational evidence support a benign effect (MetaRNN=0.34754464).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
COL12A1 | NM_004370.6 | c.7048G>T | p.Val2350Leu | missense_variant | 44/66 | ENST00000322507.13 | NP_004361.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
COL12A1 | ENST00000322507.13 | c.7048G>T | p.Val2350Leu | missense_variant | 44/66 | 1 | NM_004370.6 | ENSP00000325146.8 | ||
COL12A1 | ENST00000345356.10 | c.3556G>T | p.Val1186Leu | missense_variant | 29/51 | 1 | ENSP00000305147.9 | |||
COL12A1 | ENST00000483888.6 | c.7048G>T | p.Val2350Leu | missense_variant | 44/65 | 5 | ENSP00000421216.1 | |||
COL12A1 | ENST00000416123.6 | c.7048G>T | p.Val2350Leu | missense_variant | 43/63 | 5 | ENSP00000412864.2 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.0000161 AC: 4AN: 249068Hom.: 0 AF XY: 0.0000222 AC XY: 3AN XY: 135128
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GnomAD4 exome AF: 0.0000473 AC: 69AN: 1459486Hom.: 0 Cov.: 32 AF XY: 0.0000455 AC XY: 33AN XY: 725998
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152140Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | Jan 26, 2024 | - - |
Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 31, 2023 | This sequence change replaces valine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 2350 of the COL12A1 protein (p.Val2350Leu). This variant is present in population databases (rs755159927, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 583015). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL12A1 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;.;.;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D;D;D;D
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T;T
MetaSVM
Uncertain
T
MutationAssessor
Benign
.;L;.;L;.
PrimateAI
Uncertain
T
PROVEAN
Benign
.;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
.;D;D;D;D
Sift4G
Uncertain
D;D;D;D;D
Polyphen
0.40, 0.63
.;B;P;.;.
Vest4
MutPred
0.73
.;Loss of catalytic residue at V2350 (P = 0.0708);.;Loss of catalytic residue at V2350 (P = 0.0708);Loss of catalytic residue at V2350 (P = 0.0708);
MVP
MPC
0.97
ClinPred
D
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Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at