rs185171880

Variant names:

• chr6-75095118-T-C
• rs185171880
• NM_004370.6:c.8639A>G

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004370.6(COL12A1):​c.8639A>G​(p.His2880Arg) variant causes a missense change. The variant allele was found at a frequency of 0.000297 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00029 (0 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:4
• Conservation: PhyloP100: 3.94
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.025645465).
• BP6: Variant 6-75095118-T-C is Benign according to our data. Variant chr6-75095118-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475905.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000335 (51/152356) while in subpopulation AMR AF = 0.00163 (25/15302). AF 95% confidence interval is 0.00114. There are 0 homozygotes in GnomAd4. There are 26 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.8639A>G	p.His2880Arg	missense	Exon 60 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.8639A>G	p.His2880Arg	missense	Exon 60 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.8618A>G	p.His2873Arg	missense	Exon 59 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.8639A>G	p.His2880Arg	missense	Exon 60 of 66	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.5147A>G	p.His1716Arg	missense	Exon 45 of 51	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.8627A>G	p.His2876Arg	missense	Exon 60 of 65	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.000335 AC: 51 AN: 152238 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000469 AC: 117 AN: 249442 AF XY: 0.000488

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00160

Gnomad ASJ exome AF: 0.00169

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000309

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.000293 AC: 428 AN: 1461810 Hom.: 0 Cov.: 30 AF XY: 0.000275 AC XY: 200 AN XY: 727198

African (AFR) AF: 0.0000597 AC: 2 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.000255 AC: 283 AN: 1111968

Other (OTH) AF: 0.000629 AC: 38 AN: 60390

GnomAD4 genome AF: 0.000335 AC: 51 AN: 152356 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74514

African (AFR) AF: 0.0000962 AC: 4 AN: 41586

American (AMR) AF: 0.00163 AC: 25 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68030

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000317 Hom.: 0

Bravo AF: 0.000476

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000262 AC: 1

ESP6500EA AF: 0.000604 AC: 5

ExAC AF: 0.000438 AC: 53

EpiCase AF: 0.000382

EpiControl AF: 0.000296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 (1)
-	-	1	COL12A1-related disorder (1)
-	1	-	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.066
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	18
DANN	Benign	0.81
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.029	D
MetaRNN	Benign	0.026	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	-0.81	N
PhyloP100		3.9
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.48	N
REVEL	Uncertain	0.31
Sift	Benign	0.57	T
Sift4G	Benign	0.56	T
Polyphen		0.0010	B
Vest4		0.15
MVP		0.52
MPC		0.58
ClinPred		0.028	T
GERP RS		5.6
Varity_R		0.063
gMVP		0.36
Mutation Taster		=87/13	polymorphism

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: rs185171880; hg19: chr6-75804834;