6-75087586-C-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004370.6(COL12A1):​c.9172G>A​(p.Gly3058Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.76 in 1,613,022 control chromosomes in the GnomAD database, including 468,079 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3058N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.73 ( 40316 hom., cov: 30)
Exomes 𝑓: 0.76 ( 427763 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

3
6
9

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 7.57

Publications

69 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: Benign. The variant received -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=3.371506E-6).
BP6
Variant 6-75087586-C-T is Benign according to our data. Variant chr6-75087586-C-T is described in ClinVar as [Benign]. Clinvar id is 259358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BA1
GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.772 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL12A1NM_004370.6 linkc.9172G>A p.Gly3058Ser missense_variant Exon 65 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.9172G>A p.Gly3058Ser missense_variant Exon 65 of 66 1 NM_004370.6 ENSP00000325146.8 Q99715-1

Frequencies

GnomAD3 genomes
AF:
0.726
AC:
110227
AN:
151856
Hom.:
40303
Cov.:
30
show subpopulations
Gnomad AFR
AF:
0.656
Gnomad AMI
AF:
0.618
Gnomad AMR
AF:
0.764
Gnomad ASJ
AF:
0.762
Gnomad EAS
AF:
0.664
Gnomad SAS
AF:
0.680
Gnomad FIN
AF:
0.656
Gnomad MID
AF:
0.687
Gnomad NFE
AF:
0.778
Gnomad OTH
AF:
0.742
GnomAD2 exomes
AF:
0.747
AC:
185847
AN:
248804
AF XY:
0.741
show subpopulations
Gnomad AFR exome
AF:
0.657
Gnomad AMR exome
AF:
0.837
Gnomad ASJ exome
AF:
0.761
Gnomad EAS exome
AF:
0.662
Gnomad FIN exome
AF:
0.670
Gnomad NFE exome
AF:
0.779
Gnomad OTH exome
AF:
0.749
GnomAD4 exome
AF:
0.764
AC:
1115636
AN:
1461048
Hom.:
427763
Cov.:
56
AF XY:
0.761
AC XY:
552931
AN XY:
726870
show subpopulations
African (AFR)
AF:
0.647
AC:
21620
AN:
33404
American (AMR)
AF:
0.826
AC:
36848
AN:
44606
Ashkenazi Jewish (ASJ)
AF:
0.767
AC:
20040
AN:
26120
East Asian (EAS)
AF:
0.661
AC:
26214
AN:
39640
South Asian (SAS)
AF:
0.671
AC:
57797
AN:
86156
European-Finnish (FIN)
AF:
0.677
AC:
36133
AN:
53396
Middle Eastern (MID)
AF:
0.668
AC:
3828
AN:
5734
European-Non Finnish (NFE)
AF:
0.781
AC:
867918
AN:
1111628
Other (OTH)
AF:
0.749
AC:
45238
AN:
60364
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.465
Heterozygous variant carriers
0
14066
28132
42197
56263
70329
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Exome Hom
Variant carriers
0
20538
41076
61614
82152
102690
<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
AF:
0.726
AC:
110286
AN:
151974
Hom.:
40316
Cov.:
30
AF XY:
0.718
AC XY:
53347
AN XY:
74264
show subpopulations
African (AFR)
AF:
0.656
AC:
27169
AN:
41422
American (AMR)
AF:
0.764
AC:
11680
AN:
15282
Ashkenazi Jewish (ASJ)
AF:
0.762
AC:
2645
AN:
3472
East Asian (EAS)
AF:
0.664
AC:
3407
AN:
5130
South Asian (SAS)
AF:
0.680
AC:
3276
AN:
4816
European-Finnish (FIN)
AF:
0.656
AC:
6927
AN:
10556
Middle Eastern (MID)
AF:
0.673
AC:
198
AN:
294
European-Non Finnish (NFE)
AF:
0.777
AC:
52851
AN:
67980
Other (OTH)
AF:
0.744
AC:
1571
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.502
Heterozygous variant carriers
0
1497
2995
4492
5990
7487
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Genome Hom
Variant carriers
0
846
1692
2538
3384
4230
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
Alfa
AF:
0.765
Hom.:
188659
Bravo
AF:
0.734
TwinsUK
AF:
0.786
AC:
2914
ALSPAC
AF:
0.784
AC:
3020
ESP6500AA
AF:
0.659
AC:
2515
ESP6500EA
AF:
0.784
AC:
6486
ExAC
AF:
0.745
AC:
89988
Asia WGS
AF:
0.668
AC:
2327
AN:
3478
EpiCase
AF:
0.773
EpiControl
AF:
0.771

ClinVar

Significance: Benign
Submissions summary: Benign:7
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
-
PreventionGenetics, part of Exact Sciences
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance:Benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

- -

Bethlem myopathy 2 Benign:1
Jul 22, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Benign:1
Jul 09, 2018
GeneDx
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 16741161) -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1
Feb 04, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Ullrich congenital muscular dystrophy 2 Benign:1
Jul 22, 2021
Genome-Nilou Lab
Significance:Benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.17
BayesDel_addAF
Benign
-0.26
T
BayesDel_noAF
Uncertain
-0.010
CADD
Pathogenic
28
DANN
Uncertain
1.0
DEOGEN2
Benign
0.028
.;T;T;.;.;.
Eigen
Pathogenic
0.80
Eigen_PC
Pathogenic
0.82
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.85
T;T;T;T;T;T
MetaRNN
Benign
0.0000034
T;T;T;T;T;T
MetaSVM
Uncertain
0.56
D
MutationAssessor
Benign
2.0
.;.;M;.;.;.
PhyloP100
7.6
PrimateAI
Uncertain
0.78
T
PROVEAN
Benign
-1.5
N;.;N;N;N;N
REVEL
Uncertain
0.45
Sift
Uncertain
0.023
D;.;T;D;D;T
Sift4G
Benign
0.13
T;D;D;D;D;D
Polyphen
1.0
.;.;D;D;.;.
Vest4
0.44, 0.24, 0.56, 0.48, 0.45
MPC
1.4
ClinPred
0.016
T
GERP RS
5.8
Varity_R
0.26
gMVP
0.76
Mutation Taster
=83/17
polymorphism (auto)

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

Other links and lift over

dbSNP: rs970547; hg19: chr6-75797302; COSMIC: COSV59392062; COSMIC: COSV59392062; API