rs779184954

Positions:

• chr6-75101628-G-A
• chr6-75101628-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_004370.6(COL12A1):​c.8495C>T​(p.Pro2832Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.72

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 Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL12A1	NM_004370.6	c.8495C>T	p.Pro2832Leu	missense_variant	58/66	ENST00000322507.13	NP_004361.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL12A1	ENST00000322507.13	c.8495C>T	p.Pro2832Leu	missense_variant	58/66	1	NM_004370.6	ENSP00000325146	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249180 Hom.: 0 AF XY: 0.00000740 AC XY: 1 AN XY: 135204

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.094	.;T;D;.;.;.
Eigen	Benign	0.077
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.89	D;D;D;D;D;D
M_CAP	Uncertain	0.094	D
MetaRNN	Uncertain	0.55	D;D;D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.8	.;.;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-4.4	D;.;D;D;D;D
REVEL	Uncertain	0.50
Sift	Benign	0.20	T;.;T;T;T;T
Sift4G	Benign	0.47	T;T;T;T;T;T
Polyphen		0.018, 0.015	.;.;B;B;.;.
Vest4		0.37, 0.48, 0.35, 0.43, 0.40
MutPred		0.36		.;.;Loss of glycosylation at P2832 (P = 0.0144);.;.;Loss of glycosylation at P2832 (P = 0.0144);
MVP		0.81
MPC		0.72
ClinPred		0.92	D
GERP RS		5.7
Varity_R		0.14
gMVP		0.19

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: rs779184954; hg19: chr6-75811344;