21-46126476-TGGCCC-TGGCCCGGCCCGGCCCGGCCCGGCCCGGCCCGGCCC

Variant names:

• chr21-46126476-T-TGGCCCGGCCCGGCCCGGCCCGGCCCGGCCC
• rs138363207
• NM_001849.4:c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCCCGGCCCGGCC

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_001849.4(COL6A2):​c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCCCGGCCCGGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000548 in 1,459,302 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 INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.874
• Publications: 0 publications found

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

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

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• 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
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCCCGGCCCGGCC		intron_variant	Intron 26 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCCCGGCCCGGCC		intron_variant	Intron 26 of 27		NP_478054.2
COL6A2	NM_058175.3	c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCCCGGCCCGGCC		intron_variant	Intron 26 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.2423-27_2423-26insGGCCCGGCCCGGCCCGGCCCGGCCCGGCCC		intron_variant	Intron 26 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2423-27_2423-26insGGCCCGGCCCGGCCCGGCCCGGCCCGGCCC		intron_variant	Intron 26 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2423-27_2423-26insGGCCCGGCCCGGCCCGGCCCGGCCCGGCCC		intron_variant	Intron 25 of 26	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459302 Hom.: 0 Cov.: 34 AF XY: 0.00000551 AC XY: 4 AN XY: 726078

⚠️ 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: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26126

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000631 AC: 7 AN: 1110164

Other (OTH) AF: 0.0000166 AC: 1 AN: 60334

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87

Splicing

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

Other links and lift over

dbSNP: rs138363207; hg19: chr21-47546390;