rs117038107

Positions:

chr6-75125144-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_004370.6(COL12A1):c.6590C>T(p.Thr2197Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,610,238 control chromosomes in the GnomAD database, including 106 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0077 ( 5 hom., cov: 32)

Exomes 𝑓: 0.011 ( 101 hom. )

Consequence

COL12A1
NM_004370.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.731

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 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=0.0041609406).

BP6

Variant 6-75125144-G-A is Benign according to our data. Variant chr6-75125144-G-A is described in ClinVar as [Benign]. Clinvar id is 475889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75125144-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00772 (1175/152224) while in subpopulation NFE AF= 0.0102 (693/67992). AF 95% confidence interval is 0.00956. There are 5 homozygotes in gnomad4. There are 578 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6 linkuse as main transcript	c.6590C>T	p.Thr2197Ile	missense_variant	40/66	ENST00000322507.13	NP_004361.3	Q99715-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
COL12A1	ENST00000322507.13 linkuse as main transcript	c.6590C>T	p.Thr2197Ile	missense_variant	40/66	1	NM_004370.6	ENSP00000325146.8	Q99715-1
COL12A1	ENST00000345356.10 linkuse as main transcript	c.3098C>T	p.Thr1033Ile	missense_variant	25/51	1		ENSP00000305147.9	Q99715-2
COL12A1	ENST00000483888.6 linkuse as main transcript	c.6590C>T	p.Thr2197Ile	missense_variant	40/65	5		ENSP00000421216.1	D6RGG3
COL12A1	ENST00000416123.6 linkuse as main transcript	c.6590C>T	p.Thr2197Ile	missense_variant	39/63	5		ENSP00000412864.2	Q99715-4

Frequencies

GnomAD3 genomes

AF:

0.00773

AC:

1176

AN:

152106

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00439

Gnomad AMR

AF:

0.00609

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00952

Gnomad FIN

AF:

0.0207

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0102

Gnomad OTH

AF:

0.0110

GnomAD3 exomes

AF:

0.00868

AC:

2138

AN:

246304

Hom.:

AF XY:

0.00916

AC XY:

1224

AN XY:

133638

show subpopulations

Gnomad AFR exome

AF:

0.00143

Gnomad AMR exome

AF:

0.00321

Gnomad ASJ exome

AF:

0.00291

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0110

Gnomad FIN exome

AF:

0.0202

Gnomad NFE exome

AF:

0.0105

Gnomad OTH exome

AF:

0.00726

GnomAD4 exome

AF:

0.0108

AC:

15689

AN:

1458014

Hom.:

101

Cov.:

AF XY:

0.0108

AC XY:

7813

AN XY:

725210

show subpopulations

Gnomad4 AFR exome

AF:

0.00123

Gnomad4 AMR exome

AF:

0.00352

Gnomad4 ASJ exome

AF:

0.00346

Gnomad4 EAS exome

AF:

0.0000253

Gnomad4 SAS exome

AF:

0.0101

Gnomad4 FIN exome

AF:

0.0197

Gnomad4 NFE exome

AF:

0.0116

Gnomad4 OTH exome

AF:

0.0106

GnomAD4 genome

AF:

0.00772

AC:

1175

AN:

152224

Hom.:

Cov.:

AF XY:

0.00777

AC XY:

578

AN XY:

74428

show subpopulations

Gnomad4 AFR

AF:

0.00202

Gnomad4 AMR

AF:

0.00608

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00932

Gnomad4 FIN

AF:

0.0207

Gnomad4 NFE

AF:

0.0102

Gnomad4 OTH

AF:

0.0109

Alfa

AF:

0.00864

Hom.:

Bravo

AF:

0.00637

TwinsUK

AF:

0.0111

AC:

ALSPAC

AF:

0.0132

AC:

ESP6500AA

AF:

0.00263

AC:

ESP6500EA

AF:

0.0119

AC:

ExAC

AF:

0.00904

AC:

1093

Asia WGS

AF:

0.00376

AC:

AN:

3476

EpiCase

AF:

0.0102

EpiControl

AF:

0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	COL12A1: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 2019	- -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.071

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.026

T;T;.;.;.

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.85

T;T;T;T;T

MetaRNN

Benign

0.0042

T;T;T;T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

0.89

.;L;.;L;.

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.0

.;N;N;N;N

REVEL

Benign

0.012

Sift

Benign

0.15

.;T;T;T;T

Sift4G

Benign

0.30

T;T;T;T;T

Polyphen

0.0070, 0.012

.;B;B;.;.

Vest4

0.13

MVP

0.21

MPC

0.51

ClinPred

0.0035

GERP RS

3.4

Varity_R

0.082

gMVP

0.38

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over