6-75181216-T-TA

Variant names:

• chr6-75181216-T-TA
• rs752652515
• NM_004370.6:c.1892-6_1892-5insT

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP6_Moderate

The NM_004370.6(COL12A1):​c.1892-6_1892-5insT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000668 in 1,406,404 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 Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 25)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: COL12A1 NM_004370.6 splice_region, intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.52
• 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: 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: Likely_benign. The variant received -2 ACMG points.

• BP6: Variant 6-75181216-T-TA is Benign according to our data. Variant chr6-75181216-T-TA is described in ClinVar as Benign. ClinVar VariationId is 1165668.Status of the report is criteria_provided_single_submitter, 1 stars.

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.1892-6_1892-5insT		splice_region intron	N/A	NP_004361.3
	COL12A1	NM_001424113.1		c.1892-6_1892-5insT		splice_region intron	N/A	NP_001411042.1
	COL12A1	NM_001424114.1		c.1892-6_1892-5insT		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.1892-6_1892-5insT		splice_region intron	N/A	ENSP00000325146.8
	COL12A1	ENST00000345356.10	TSL:1	c.73+21503_73+21504insT		intron	N/A	ENSP00000305147.9
	COL12A1	ENST00000486533.1	TSL:1	n.998-6_998-5insT		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.000430 AC: 8 AN: 18588 Hom.: 0 Cov.: 25

Gnomad AFR AF: 0.000313

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00410

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00147

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000596

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000194 AC: 20 AN: 103032 AF XY: 0.000180

Gnomad AFR exome AF: 0.000311

Gnomad AMR exome AF: 0.000256

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000107

Gnomad FIN exome AF: 0.000111

Gnomad NFE exome AF: 0.000208

Gnomad OTH exome AF: 0.000419

GnomAD4 exome AF: 0.0000620 AC: 86 AN: 1387792 Hom.: 0 Cov.: 28 AF XY: 0.0000770 AC XY: 53 AN XY: 688080

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30164

American (AMR) AF: 0.0000897 AC: 3 AN: 33452

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23770

East Asian (EAS) AF: 0.0000262 AC: 1 AN: 38164

South Asian (SAS) AF: 0.000105 AC: 8 AN: 76134

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50542

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5212

European-Non Finnish (NFE) AF: 0.0000680 AC: 73 AN: 1073408

Other (OTH) AF: 0.0000176 AC: 1 AN: 56946

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000430 AC: 8 AN: 18612 Hom.: 0 Cov.: 25 AF XY: 0.000439 AC XY: 4 AN XY: 9102

African (AFR) AF: 0.000312 AC: 4 AN: 12810

American (AMR) AF: 0.00 AC: 0 AN: 1018

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 128

East Asian (EAS) AF: 0.00420 AC: 1 AN: 238

South Asian (SAS) AF: 0.00 AC: 0 AN: 100

European-Finnish (FIN) AF: 0.00147 AC: 1 AN: 680

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 36

European-Non Finnish (NFE) AF: 0.000595 AC: 2 AN: 3362

Other (OTH) AF: 0.00 AC: 0 AN: 196

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 2;C4225314:Ullrich congenital muscular dystrophy 2 Benign:1

Aug 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5
Mutation Taster		=88/12	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: rs752652515; hg19: chr6-75890932;