rs199724285

chr6-75115791-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS1

The NM_004370.6(COL12A1):c.7690C>T(p.Pro2564Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000684 in 1,609,286 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00039 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000034 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 9.52

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, COL12A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.037420213).
• BP6: Variant 6-75115791-G-A is Benign according to our data. Variant chr6-75115791-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542500.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000394 (60/152240) while in subpopulation AFR AF= 0.00132 (55/41546). AF 95% confidence interval is 0.00104. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL12A1	NM_004370.6	c.7690C>T	p.Pro2564Ser	missense_variant	49/66	ENST00000322507.13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL12A1	ENST00000322507.13	c.7690C>T	p.Pro2564Ser	missense_variant	49/66	1	NM_004370.6	P4

Frequencies

GnomAD3 genomes AF: 0.000394 AC: 60 AN: 152124 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000115 AC: 28 AN: 244402 Hom.: 0 AF XY: 0.0000755 AC XY: 10 AN XY: 132470

Gnomad AFR exome AF: 0.00136

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000170

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000899

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.0000343 AC: 50 AN: 1457046 Hom.: 0 Cov.: 31 AF XY: 0.0000304 AC XY: 22 AN XY: 724630

Gnomad4 AFR exome AF: 0.00106

Gnomad4 AMR exome AF: 0.0000457

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000705

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome AF: 0.000394 AC: 60 AN: 152240 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74444

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000666 Hom.: 0

Bravo AF: 0.000491

ESP6500AA AF: 0.00179 AC: 7

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000190 AC: 23

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Jun 29, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 30, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.080
Cadd	Pathogenic	27
Dann	Uncertain	1.0
Eigen	Pathogenic	0.81
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.037	T;T;T;T;T;T;T
MetaSVM	Benign	-0.84	T
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-5.1	D;.;D;D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.10	T;.;D;D;D;D;T
Sift4G	Benign	0.27	T;D;D;D;D;D;D
Polyphen		1.0	.;.;D;D;.;.;.
Vest4		0.75, 0.68, 0.69, 0.77, 0.73
MVP		0.49
MPC		1.4
ClinPred		0.14	T
GERP RS		4.8
Varity_R		0.49
gMVP		0.62

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: rs199724285; hg19: chr6-75825507;