rs796052093

Positions:

• chr6-75121387-A-G

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_004370.6(COL12A1):​c.7001T>C​(p.Ile2334Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,459,874 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:6
• Conservation: PhyloP100: 9.32

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]

ACMG classification

Verdict is Pathogenic. Variant got 13 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 6-75121387-A-G is Pathogenic according to our data. Variant chr6-75121387-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 204295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.7001T>C	p.Ile2334Thr	missense_variant	44/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.7001T>C	p.Ile2334Thr	missense_variant	44/66	1	NM_004370.6	ENSP00000325146.8
COL12A1	ENST00000345356.10	c.3509T>C	p.Ile1170Thr	missense_variant	29/51	1		ENSP00000305147.9
COL12A1	ENST00000483888.6	c.7001T>C	p.Ile2334Thr	missense_variant	44/65	5		ENSP00000421216.1
COL12A1	ENST00000416123.6	c.7001T>C	p.Ile2334Thr	missense_variant	43/63	5		ENSP00000412864.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1459874 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726212

Gnomad4 AFR exome AF: 0.00

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: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	May 28, 2020	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Mar 01, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 29858556, 31216405, 24334604) -

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 27, 2023	For these reasons, this variant has been classified as Pathogenic. 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on COL12A1 protein function. ClinVar contains an entry for this variant (Variation ID: 204295). This variant is also known as c.7167T>C. This missense change has been observed in individual(s) with autosomal dominant COL12A1-related conditions (PMID: 24334604, 29858556). In at least one individual the variant was observed to be de novo. This variant has been reported in individual(s) with autosomal recessive COL12A1-related conditions (PMID: 29858556); however, the role of the variant in this condition is currently unclear. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 2334 of the COL12A1 protein (p.Ile2334Thr). -
Likely pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Oct 12, 2018	- -

Bethlem myopathy 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

May 01, 2014

- -

Ullrich congenital muscular dystrophy 2 Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

Institute of Human Genetics, Cologne University

Apr 25, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.093	T;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D
MetaSVM	Uncertain	0.76	D
MutationAssessor	Uncertain	2.6	.;M;.;M;.
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.6	.;D;D;D;D
REVEL	Pathogenic	0.96
Sift	Uncertain	0.0010	.;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	.;D;D;.;.
Vest4		0.83
MutPred		0.66		.;Loss of stability (P = 9e-04);.;Loss of stability (P = 9e-04);Loss of stability (P = 9e-04);
MVP		0.97
MPC		1.5
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.69
gMVP		0.85

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

Other links and lift over

dbSNP: rs796052093; hg19: chr6-75831103; COSMIC: COSV59409694; COSMIC: COSV59409694;