rs190984968

chr6-75113300-C-Gchr6-75113300-C-T

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS1

The NM_004370.6(COL12A1):c.7854G>C(p.Thr2618=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000103 in 1,548,444 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T2618T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000099 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00010 (1 hom.)
• Consequence: COL12A1 NM_004370.6 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.86

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 6-75113300-C-G is Benign according to our data. Variant chr6-75113300-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 542512.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-75113300-C-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.86 with no splicing effect.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000103 (144/1396734) while in subpopulation MID AF= 0.00232 (13/5594). AF 95% confidence interval is 0.00137. There are 1 homozygotes in gnomad4_exome. There are 70 alleles in male gnomad4_exome subpopulation. Median coverage is 28. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.7854G>C	p.Thr2618=	synonymous_variant	51/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.7854G>C	p.Thr2618=	synonymous_variant	51/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.0000989 AC: 15 AN: 151592 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000726

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000197

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000738

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000101 AC: 21 AN: 206940 Hom.: 0 AF XY: 0.0000967 AC XY: 11 AN XY: 113762

Gnomad AFR exome AF: 0.0000823

Gnomad AMR exome AF: 0.000158

Gnomad ASJ exome AF: 0.000440

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000916

Gnomad OTH exome AF: 0.000626

GnomAD4 exome AF: 0.000103 AC: 144 AN: 1396734 Hom.: 1 Cov.: 28 AF XY: 0.000101 AC XY: 70 AN XY: 693640

Gnomad4 AFR exome AF: 0.00113

Gnomad4 AMR exome AF: 0.000140

Gnomad4 ASJ exome AF: 0.000848

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000135

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000424

Gnomad4 OTH exome AF: 0.000418

GnomAD4 genome AF: 0.0000989 AC: 15 AN: 151710 Hom.: 0 Cov.: 32 AF XY: 0.0000674 AC XY: 5 AN XY: 74170

Gnomad4 AFR AF: 0.0000724

Gnomad4 AMR AF: 0.000197

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000738

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000869 Hom.: 0

Bravo AF: 0.000174

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	COL12A1: BP4, BP7 -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 20, 2020	- -

COL12A1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 06, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
Cadd	Benign	0.31
Dann	Benign	0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs190984968; hg19: chr6-75823016;