rs755159927

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

Scores

12
7

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 4.81
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 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
COL12A1NM_004370.6 linkuse as main transcriptc.7048G>T p.Val2350Leu missense_variant 44/66 ENST00000322507.13 NP_004361.3 Q99715-1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL12A1ENST00000322507.13 linkuse as main transcriptc.7048G>T p.Val2350Leu missense_variant 44/661 NM_004370.6 ENSP00000325146.8 Q99715-1
COL12A1ENST00000345356.10 linkuse as main transcriptc.3556G>T p.Val1186Leu missense_variant 29/511 ENSP00000305147.9 Q99715-2
COL12A1ENST00000483888.6 linkuse as main transcriptc.7048G>T p.Val2350Leu missense_variant 44/655 ENSP00000421216.1 D6RGG3
COL12A1ENST00000416123.6 linkuse as main transcriptc.7048G>T p.Val2350Leu missense_variant 43/635 ENSP00000412864.2 Q99715-4

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152140
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000161
AC:
4
AN:
249068
Hom.:
0
AF XY:
0.0000222
AC XY:
3
AN XY:
135128
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000266
Gnomad OTH exome
AF:
0.000166
GnomAD4 exome
AF:
0.0000473
AC:
69
AN:
1459486
Hom.:
0
Cov.:
32
AF XY:
0.0000455
AC XY:
33
AN XY:
725998
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000585
Gnomad4 OTH exome
AF:
0.0000498
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152140
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74316
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000189
ExAC
AF:
0.0000165
AC:
2

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 submitterclinical testingMayo Clinic Laboratories, Mayo ClinicJan 26, 2024- -
Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 31, 2023This 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

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.45
BayesDel_addAF
Uncertain
0.038
T
BayesDel_noAF
Benign
-0.10
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.040
T;T;.;.;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.47
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Uncertain
0.94
D;D;D;D;D
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.35
T;T;T;T;T
MetaSVM
Uncertain
-0.075
T
MutationAssessor
Benign
0.97
.;L;.;L;.
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-1.5
.;N;N;N;N
REVEL
Uncertain
0.48
Sift
Uncertain
0.017
.;D;D;D;D
Sift4G
Uncertain
0.0040
D;D;D;D;D
Polyphen
0.40, 0.63
.;B;P;.;.
Vest4
0.34
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
0.86
MPC
0.97
ClinPred
0.62
D
GERP RS
5.8
Varity_R
0.30
gMVP
0.63

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: rs755159927; hg19: chr6-75831056; API