6-75131984-G-T

Variant names:

• chr6-75131984-G-T
• rs200487396
• NM_004370.6:c.5893C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004370.6(COL12A1):​c.5893C>A​(p.Arg1965Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,814 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1965H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.58
• Publications: 9 publications found

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]

COL12A1 Gene-Disease associations (from GenCC):

• Bethlem myopathy 2

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae)
• Bethlem myopathy 2

  Inheritance: AD Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Illumina, Genomics England PanelApp
• Ullrich congenital muscular dystrophy 2

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004370.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.5893C>A	p.Arg1965Ser	missense	Exon 35 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.5893C>A	p.Arg1965Ser	missense	Exon 35 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.5872C>A	p.Arg1958Ser	missense	Exon 34 of 65	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.5893C>A	p.Arg1965Ser	missense	Exon 35 of 66	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.2401C>A	p.Arg801Ser	missense	Exon 20 of 51	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.5893C>A	p.Arg1965Ser	missense	Exon 35 of 65	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461814 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111954

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.034	T
Eigen	Uncertain	0.25
Eigen_PC	Benign	0.16
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.026	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.6
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-2.5	D
REVEL	Uncertain	0.41
Sift	Uncertain	0.011	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.98	D
Vest4		0.45
MutPred		0.60		Gain of glycosylation at R1965 (P = 0.0289)
MVP		0.50
MPC		0.49
ClinPred		0.98	D
GERP RS		5.3
Varity_R		0.34
gMVP		0.76
Mutation Taster		=29/71	disease causing

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

Other links and lift over

dbSNP: rs200487396; hg19: chr6-75841700;