rs201852681

Variant names:

• chr6-75156305-T-C
• rs201852681
• NM_004370.6:c.3202A>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.3202A>G​(p.Ile1068Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000237 in 1,613,884 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 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 0.00042 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (1 hom.)
• Consequence: COL12A1 NM_004370.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.212
• Publications: 3 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: Labcorp Genetics (formerly Invitae), Orphanet
• 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=0.026756734).
• BP6: Variant 6-75156305-T-C is Benign according to our data. Variant chr6-75156305-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 475857.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00042 (64/152270) while in subpopulation AMR AF = 0.00268 (41/15298). AF 95% confidence interval is 0.00203. There are 0 homozygotes in GnomAd4. There are 37 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	NM_004370.6	MANE Select	c.3202A>G	p.Ile1068Val	missense	Exon 15 of 66	NP_004361.3
	COL12A1	NM_001424113.1		c.3202A>G	p.Ile1068Val	missense	Exon 15 of 66	NP_001411042.1
	COL12A1	NM_001424114.1		c.3202A>G	p.Ile1068Val	missense	Exon 15 of 65	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.3202A>G	p.Ile1068Val	missense	Exon 15 of 66	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.74-3823A>G		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000483888.6	TSL:5	c.3202A>G	p.Ile1068Val	missense	Exon 15 of 65	ENSP00000421216.1

Frequencies

GnomAD3 genomes AF: 0.000421 AC: 64 AN: 152152 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

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: 0.000250

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.000373 AC: 93 AN: 249288 AF XY: 0.000288

Gnomad AFR exome AF: 0.0000646

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000248

Gnomad OTH exome AF: 0.000496

GnomAD4 exome AF: 0.000218 AC: 319 AN: 1461614 Hom.: 1 Cov.: 33 AF XY: 0.000206 AC XY: 150 AN XY: 727112

African (AFR) AF: 0.0000598 AC: 2 AN: 33454

American (AMR) AF: 0.00172 AC: 77 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000197 AC: 219 AN: 1111818

Other (OTH) AF: 0.000348 AC: 21 AN: 60378

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152270 Hom.: 0 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74460

African (AFR) AF: 0.0000481 AC: 2 AN: 41566

American (AMR) AF: 0.00268 AC: 41 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000250 AC: 17 AN: 68000

Other (OTH) AF: 0.00190 AC: 4 AN: 2110

Alfa AF: 0.000363 Hom.: 2

Bravo AF: 0.000555

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000121 AC: 1

ExAC AF: 0.000281 AC: 34

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.35
DANN	Benign	0.15
DEOGEN2	Benign	0.044	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.084	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.027	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.070	N
PhyloP100		0.21
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.044
Sift	Benign	0.61	T
Sift4G	Benign	0.55	T
Polyphen		0.0	B
Vest4		0.073
MVP		0.14
MPC		0.099
ClinPred		0.015	T
GERP RS		-1.4
Varity_R		0.034
gMVP		0.19
Mutation Taster		=93/7	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: rs201852681; hg19: chr6-75866021;