rs778958906

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2PP2PP3_Moderate

The NM_004370.6(COL12A1):​c.7025T>C​(p.Val2342Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

COL12A1
NM_004370.6 missense

Scores

10
6
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.32
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.847

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL12A1NM_004370.6 linkuse as main transcriptc.7025T>C p.Val2342Ala missense_variant 44/66 ENST00000322507.13 NP_004361.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL12A1ENST00000322507.13 linkuse as main transcriptc.7025T>C p.Val2342Ala missense_variant 44/661 NM_004370.6 ENSP00000325146 P4Q99715-1
COL12A1ENST00000345356.10 linkuse as main transcriptc.3533T>C p.Val1178Ala missense_variant 29/511 ENSP00000305147 Q99715-2
COL12A1ENST00000483888.6 linkuse as main transcriptc.7025T>C p.Val2342Ala missense_variant 44/655 ENSP00000421216 A1
COL12A1ENST00000416123.6 linkuse as main transcriptc.7025T>C p.Val2342Ala missense_variant 43/635 ENSP00000412864 Q99715-4

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMay 27, 2023In 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. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL12A1 protein function. ClinVar contains an entry for this variant (Variation ID: 572611). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. This variant is present in population databases (rs778958906, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 2342 of the COL12A1 protein (p.Val2342Ala). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.40
D
BayesDel_noAF
Pathogenic
0.33
CADD
Pathogenic
27
DANN
Uncertain
1.0
DEOGEN2
Benign
0.084
T;D;.;.;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.80
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.96
D;D;D;D;D
M_CAP
Benign
0.071
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D
MetaSVM
Uncertain
0.39
D
MutationAssessor
Uncertain
2.1
.;M;.;M;.
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.82
D
PROVEAN
Uncertain
-2.9
.;D;D;D;D
REVEL
Pathogenic
0.87
Sift
Uncertain
0.021
.;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D
Polyphen
1.0
.;D;D;.;.
Vest4
0.76
MutPred
0.70
.;Loss of methylation at K2341 (P = 0.0501);.;Loss of methylation at K2341 (P = 0.0501);Loss of methylation at K2341 (P = 0.0501);
MVP
0.95
MPC
1.5
ClinPred
0.93
D
GERP RS
5.8
Varity_R
0.60
gMVP
0.74

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: rs778958906; hg19: chr6-75831079; API