rs117038107

chr6-75125144-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.731

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 Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• 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 GnomAd at 5 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.6590C>T	p.Thr2197Ile	missense_variant	40/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.6590C>T	p.Thr2197Ile	missense_variant	40/66	1	NM_004370.6	P4
COL12A1	ENST00000345356.10	c.3098C>T	p.Thr1033Ile	missense_variant	25/51	1
COL12A1	ENST00000483888.6	c.6590C>T	p.Thr2197Ile	missense_variant	40/65	5		A1
COL12A1	ENST00000416123.6	c.6590C>T	p.Thr2197Ile	missense_variant	39/63	5

Frequencies

GnomAD3 genomes AF: 0.00773 AC: 1176 AN: 152106 Hom.: 5 Cov.: 32

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.: 17 AF XY: 0.00916 AC XY: 1224 AN XY: 133638

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.: 30 AF XY: 0.0108 AC XY: 7813 AN XY: 725210

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.: 5 Cov.: 32 AF XY: 0.00777 AC XY: 578 AN XY: 74428

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.: 9

Bravo AF: 0.00637

TwinsUK AF: 0.0111 AC: 41

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00263 AC: 10

ESP6500EA AF: 0.0119 AC: 98

ExAC AF: 0.00904 AC: 1093

Asia WGS AF: 0.00376 AC: 13 AN: 3476

EpiCase AF: 0.0102

EpiControl AF: 0.0105

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

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

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	17
Dann	Uncertain	0.99
DEOGEN2	Benign	0.026	T;T;.;.;.
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.14
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	T;T;T;T;T
MetaRNN	Benign	0.0042	T;T;T;T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.47	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	T
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

Other links and lift over

dbSNP: rs117038107; hg19: chr6-75834860;