6-75194833-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_004370.6(COL12A1):​c.188C>G​(p.Thr63Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Consequence

COL12A1
NM_004370.6 missense, splice_region

Scores

1
3
15
Splicing: ADA: 0.007909
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.56
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.28215402).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL12A1NM_004370.6 linkuse as main transcriptc.188C>G p.Thr63Arg missense_variant, splice_region_variant 3/66 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.188C>G p.Thr63Arg missense_variant, splice_region_variant 3/661 NM_004370.6 ENSP00000325146.8 Q99715-1
COL12A1ENST00000345356.10 linkuse as main transcriptc.73+7887C>G intron_variant 1 ENSP00000305147.9 Q99715-2
COL12A1ENST00000483888.6 linkuse as main transcriptc.188C>G p.Thr63Arg missense_variant, splice_region_variant 3/655 ENSP00000421216.1 D6RGG3
COL12A1ENST00000416123.6 linkuse as main transcriptc.188C>G p.Thr63Arg missense_variant, splice_region_variant 2/635 ENSP00000412864.2 Q99715-4

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
Cov.:
28
GnomAD4 genome
Cov.:
33
Bravo
AF:
0.00000756

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), LabcorpJun 20, 2023This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 63 of the COL12A1 protein (p.Thr63Arg). 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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Benign
-0.30
CADD
Uncertain
24
DANN
Uncertain
0.98
DEOGEN2
Benign
0.14
T;.;.
Eigen
Benign
0.17
Eigen_PC
Benign
0.22
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Uncertain
0.88
D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.28
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
1.3
L;L;.
PrimateAI
Benign
0.43
T
PROVEAN
Benign
-1.3
N;N;N
REVEL
Benign
0.12
Sift
Benign
0.27
T;T;T
Sift4G
Uncertain
0.024
D;D;D
Polyphen
0.94
P;.;.
Vest4
0.47
MutPred
0.34
Loss of glycosylation at T63 (P = 0.0052);Loss of glycosylation at T63 (P = 0.0052);Loss of glycosylation at T63 (P = 0.0052);
MVP
0.59
MPC
0.35
ClinPred
0.75
D
GERP RS
4.8
Varity_R
0.11
gMVP
0.58

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0079
dbscSNV1_RF
Benign
0.17
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: rs374544349; hg19: chr6-75904549; API