rs141102808

Variant names:

• chr6-75113758-CAAAAG-C
• rs141102808
• NM_004370.6:c.7698-19_7698-15delCTTTT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004370.6(COL12A1):​c.7698-19_7698-15delCTTTT variant causes a intron change. The variant allele was found at a frequency of 0.0141 in 1,500,544 control chromosomes in the GnomAD database, including 165 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (10 hom., cov: 32)
  • Exomes 𝑓: 0.014 (155 hom.)
• Consequence: COL12A1 NM_004370.6 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.65
• Publications: 0 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: Genomics England PanelApp, Ambry Genetics, Illumina
• 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 -16 ACMG points.

• BP6: Variant 6-75113758-CAAAAG-C is Benign according to our data. Variant chr6-75113758-CAAAAG-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259346.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 = 0.0111 (1560/140206) while in subpopulation NFE AF = 0.0183 (1148/62890). AF 95% confidence interval is 0.0174. There are 10 homozygotes in GnomAd4. There are 759 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

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.7698-19_7698-15delCTTTT		intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.7698-19_7698-15delCTTTT		intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.7677-19_7677-15delCTTTT		intron	N/A	NP_001411043.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL12A1	ENST00000322507.13	TSL:1 MANE Select	c.7698-19_7698-15delCTTTT		intron	N/A	ENSP00000325146.8	Q99715-1
	COL12A1	ENST00000345356.10	TSL:1	c.4206-19_4206-15delCTTTT		intron	N/A	ENSP00000305147.9	Q99715-2
	COL12A1	ENST00000483888.6	TSL:5	c.7698-19_7698-15delCTTTT		intron	N/A	ENSP00000421216.1	D6RGG3

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1560 AN: 140082 Hom.: 10 Cov.: 32

Gnomad AFR AF: 0.00272

Gnomad AMI AF: 0.00239

Gnomad AMR AF: 0.00656

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00188

Gnomad FIN AF: 0.0185

Gnomad MID AF: 0.00355

Gnomad NFE AF: 0.0183

Gnomad OTH AF: 0.0117

GnomAD2 exomes AF: 0.0107 AC: 2214 AN: 206878 AF XY: 0.0108

Gnomad AFR exome AF: 0.00262

Gnomad AMR exome AF: 0.00481

Gnomad ASJ exome AF: 0.000390

Gnomad EAS exome AF: 0.0000693

Gnomad FIN exome AF: 0.0174

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0134

GnomAD4 exome AF: 0.0145 AC: 19657 AN: 1360338 Hom.: 155 AF XY: 0.0141 AC XY: 9538 AN XY: 674160

African (AFR) AF: 0.00174 AC: 52 AN: 29892

American (AMR) AF: 0.00462 AC: 157 AN: 33984

Ashkenazi Jewish (ASJ) AF: 0.000441 AC: 10 AN: 22678

East Asian (EAS) AF: 0.0000267 AC: 1 AN: 37518

South Asian (SAS) AF: 0.00209 AC: 142 AN: 67806

European-Finnish (FIN) AF: 0.0196 AC: 971 AN: 49464

Middle Eastern (MID) AF: 0.00151 AC: 8 AN: 5308

European-Non Finnish (NFE) AF: 0.0167 AC: 17633 AN: 1058200

Other (OTH) AF: 0.0123 AC: 683 AN: 55488

GnomAD4 genome AF: 0.0111 AC: 1560 AN: 140206 Hom.: 10 Cov.: 32 AF XY: 0.0111 AC XY: 759 AN XY: 68518

African (AFR) AF: 0.00271 AC: 103 AN: 38048

American (AMR) AF: 0.00655 AC: 93 AN: 14208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3238

East Asian (EAS) AF: 0.00 AC: 0 AN: 4688

South Asian (SAS) AF: 0.00189 AC: 8 AN: 4244

European-Finnish (FIN) AF: 0.0185 AC: 183 AN: 9888

Middle Eastern (MID) AF: 0.00379 AC: 1 AN: 264

European-Non Finnish (NFE) AF: 0.0183 AC: 1148 AN: 62890

Other (OTH) AF: 0.0116 AC: 22 AN: 1902

Alfa AF: 0.0137 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=98/2	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs141102808;

hg19: chr6-75823474;