rs776138916

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004370.6(COL12A1):​c.9185C>T​(p.Ser3062Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000206 in 1,453,068 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S3062S) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

1
7
11

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.46

Publications

0 publications found
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]
COL12A1 Gene-Disease associations (from GenCC):
  • Bethlem myopathy 2
    Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet
  • Bethlem myopathy 2
    Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
  • Ullrich congenital muscular dystrophy 2
    Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
  • Bethlem myopathy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • Ullrich congenital muscular dystrophy
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.12791586).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL12A1NM_004370.6 linkc.9185C>T p.Ser3062Phe missense_variant Exon 66 of 66 ENST00000322507.13 NP_004361.3 Q99715-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL12A1ENST00000322507.13 linkc.9185C>T p.Ser3062Phe missense_variant Exon 66 of 66 1 NM_004370.6 ENSP00000325146.8 Q99715-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD2 exomes
AF:
0.00
AC:
0
AN:
248332
AF XY:
0.00
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 FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1453068
Hom.:
0
Cov.:
29
AF XY:
0.00000277
AC XY:
2
AN XY:
723126
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33204
American (AMR)
AF:
0.00
AC:
0
AN:
44282
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
25842
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39224
South Asian (SAS)
AF:
0.0000350
AC:
3
AN:
85610
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
52506
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5742
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
1106854
Other (OTH)
AF:
0.00
AC:
0
AN:
59804
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.508
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
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
Dec 11, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is not present in population databases (gnomAD no frequency). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 3062 of the COL12A1 protein (p.Ser3062Phe). This variant has not been reported in the literature in individuals affected with COL12A1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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
Benign
0.093
BayesDel_addAF
Uncertain
0.071
D
BayesDel_noAF
Benign
-0.14
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Benign
0.013
T;T;.;.
Eigen
Benign
-0.025
Eigen_PC
Uncertain
0.23
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.76
T;T;T;T
M_CAP
Benign
0.011
T
MetaRNN
Benign
0.13
T;T;T;T
MetaSVM
Benign
-0.77
T
MutationAssessor
Benign
0.0
.;N;.;.
PhyloP100
3.5
PrimateAI
Uncertain
0.57
T
PROVEAN
Benign
-0.28
.;N;N;N
REVEL
Uncertain
0.32
Sift
Pathogenic
0.0
.;D;D;D
Sift4G
Uncertain
0.028
D;D;D;D
Polyphen
0.0020, 0.0040
.;B;B;.
Vest4
0.090
MutPred
0.31
.;Loss of glycosylation at S3062 (P = 5e-04);.;.;
MVP
0.19
MPC
1.4
ClinPred
0.54
D
GERP RS
6.2
Varity_R
0.19
gMVP
0.34
Mutation Taster
=82/18
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs776138916; hg19: chr6-75796270; API