NM_004370.6:c.1892-7_1892-6insC

Variant names:

• chr6-75181217-T-TG
• rs34433354
• NM_004370.6:c.1892-7_1892-6insC

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS1

The NM_004370.6(COL12A1):​c.1892-7_1892-6insC variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000275 in 1,260,014 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00022 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00028 (0 hom.)
• Consequence: COL12A1 NM_004370.6 splice_region, intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.687
• 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: 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 -12 ACMG points.

• BP6: Variant 6-75181217-T-TG is Benign according to our data. Variant chr6-75181217-T-TG is described in ClinVar as Likely_benign. ClinVar VariationId is 475846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000218 (32/146662) while in subpopulation NFE AF = 0.000435 (29/66636). AF 95% confidence interval is 0.000311. There are 0 homozygotes in GnomAd4. There are 13 alleles in the male GnomAd4 subpopulation. Median coverage is 0. 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.1892-7_1892-6insC		splice_region intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.1892-7_1892-6insC		splice_region intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.1892-7_1892-6insC		splice_region intron	N/A	NP_001411043.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.1892-7_1892-6insC		splice_region intron	N/A	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.73+21502_73+21503insC		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000486533.1	TSL:1	n.998-7_998-6insC		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000218 AC: 32 AN: 146662 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000251

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000215

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000435

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000283 AC: 315 AN: 1113352 Hom.: 0 Cov.: 30 AF XY: 0.000287 AC XY: 159 AN XY: 553396

African (AFR) AF: 0.0000368 AC: 1 AN: 27176

American (AMR) AF: 0.0000364 AC: 1 AN: 27482

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19868

East Asian (EAS) AF: 0.00 AC: 0 AN: 33594

South Asian (SAS) AF: 0.000257 AC: 17 AN: 66194

European-Finnish (FIN) AF: 0.000128 AC: 5 AN: 39094

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3792

European-Non Finnish (NFE) AF: 0.000334 AC: 284 AN: 849190

Other (OTH) AF: 0.000149 AC: 7 AN: 46962

GnomAD4 genome AF: 0.000218 AC: 32 AN: 146662 Hom.: 0 Cov.: 0 AF XY: 0.000183 AC XY: 13 AN XY: 71176

African (AFR) AF: 0.0000251 AC: 1 AN: 39920

American (AMR) AF: 0.00 AC: 0 AN: 14768

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3416

East Asian (EAS) AF: 0.00 AC: 0 AN: 5084

South Asian (SAS) AF: 0.000215 AC: 1 AN: 4662

European-Finnish (FIN) AF: 0.000112 AC: 1 AN: 8940

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 312

European-Non Finnish (NFE) AF: 0.000435 AC: 29 AN: 66636

Other (OTH) AF: 0.00 AC: 0 AN: 2014

Alfa AF: 0.000169 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.69

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: rs34433354; hg19: chr6-75890933;