rs1556425727

Variant names:

• chr21-45990407-GGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA-G
• rs1556425727
• NM_001848.3:c.1002+6_1002+88delTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGAGTGGACGGCGTGAAGGTGAC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PVS1_Moderate BP6_Moderate BS1

The ENST00000361866.8(COL6A1):​c.988_1002+68delGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA​(p.Val330_Lys334del) variant causes a splice donor, conservative inframe deletion, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000132 in 1,294,916 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00013 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL6A1 ENST00000361866.8 splice_donor, conservative_inframe_deletion, splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 8.34
• Publications: 0 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• collagen 6-related myopathy

  Inheritance: SD, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.014577259 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 21-45990407-GGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA-G is Benign according to our data. Variant chr21-45990407-GGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA-G is described in ClinVar as Likely_benign. ClinVar VariationId is 543025.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000132 (171/1294916) while in subpopulation MID AF = 0.000597 (3/5024). AF 95% confidence interval is 0.000162. There are 0 homozygotes in GnomAdExome4. There are 78 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000361866.8. 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
	COL6A1	NM_001848.3	MANE Select	c.1002+6_1002+88delTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGAGTGGACGGCGTGAAGGTGAC		splice_region intron	N/A	NP_001839.2	P12109

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.988_1002+68delGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA	p.Val330_Lys334del	splice_donor conservative_inframe_deletion splice_region intron	Exon 13 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.564+3747_564+3829delGTGGACGGCGTGAAGGTGACTGGGGGGAGATAGGATGGACGGGGAGGGACGAGGAGGAATGGGGCGAGATGGGGAGGGACGGA		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 173 AN: 48458 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00400

Gnomad AMI AF: 0.00617

Gnomad AMR AF: 0.00429

Gnomad ASJ AF: 0.00334

Gnomad EAS AF: 0.00202

Gnomad SAS AF: 0.00476

Gnomad FIN AF: 0.00626

Gnomad MID AF: 0.0217

Gnomad NFE AF: 0.00269

Gnomad OTH AF: 0.00318

GnomAD2 exomes AF: 0.000117 AC: 29 AN: 248642 AF XY: 0.000111

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000471

Gnomad NFE exome AF: 0.000197

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000132 AC: 171 AN: 1294916 Hom.: 0 AF XY: 0.000121 AC XY: 78 AN XY: 643186

African (AFR) AF: 0.0000347 AC: 1 AN: 28834

American (AMR) AF: 0.000101 AC: 4 AN: 39476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20886

East Asian (EAS) AF: 0.00 AC: 0 AN: 25876

South Asian (SAS) AF: 0.0000251 AC: 2 AN: 79674

European-Finnish (FIN) AF: 0.0000755 AC: 3 AN: 39752

Middle Eastern (MID) AF: 0.000597 AC: 3 AN: 5024

European-Non Finnish (NFE) AF: 0.000152 AC: 153 AN: 1005392

Other (OTH) AF: 0.000100 AC: 5 AN: 50002

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00357 AC: 173 AN: 48508 Hom.: 0 Cov.: 0 AF XY: 0.00382 AC XY: 89 AN XY: 23292

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

African (AFR) AF: 0.00398 AC: 54 AN: 13554

American (AMR) AF: 0.00429 AC: 18 AN: 4198

Ashkenazi Jewish (ASJ) AF: 0.00334 AC: 4 AN: 1196

East Asian (EAS) AF: 0.00203 AC: 3 AN: 1480

South Asian (SAS) AF: 0.00476 AC: 7 AN: 1470

European-Finnish (FIN) AF: 0.00626 AC: 20 AN: 3194

Middle Eastern (MID) AF: 0.0238 AC: 3 AN: 126

European-Non Finnish (NFE) AF: 0.00269 AC: 60 AN: 22322

Other (OTH) AF: 0.00311 AC: 2 AN: 644

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.000594 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A1-related disorder (1)
-	-	-	Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		8.3

Splicing

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

Other links and lift over

dbSNP: rs1556425727; hg19: chr21-47410321;