chr21-46126476-T-TGGCCC

Variant names:

• chr21-46126476-T-TGGCCC
• rs138363207
• NM_001849.4:c.2423-22_2423-18dupCGGCC

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001849.4(COL6A2):​c.2423-22_2423-18dupCGGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00818 in 1,611,530 control chromosomes in the GnomAD database, including 543 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.020 (98 hom., cov: 32)
  • Exomes 𝑓: 0.0069 (445 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.874
• Publications: 2 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, SD, 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: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 21-46126476-T-TGGCCC is Benign according to our data. Variant chr21-46126476-T-TGGCCC is described in ClinVar as Benign. ClinVar VariationId is 1241745.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0793 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. 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
	COL6A2	NM_001849.4	MANE Select	c.2423-22_2423-18dupCGGCC		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.2423-22_2423-18dupCGGCC		intron	N/A	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.2423-22_2423-18dupCGGCC		intron	N/A	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2423-27_2423-26insGGCCC		intron	N/A	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2423-27_2423-26insGGCCC		intron	N/A	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.2618-27_2618-26insGGCCC		intron	N/A	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.0199 AC: 3029 AN: 152114 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.0588

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00569

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00580

Gnomad SAS AF: 0.0863

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000368

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00694 AC: 10126 AN: 1459298 Hom.: 445 Cov.: 34 AF XY: 0.00882 AC XY: 6406 AN XY: 726074

African (AFR) AF: 0.0650 AC: 2176 AN: 33476

American (AMR) AF: 0.00349 AC: 156 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26126

East Asian (EAS) AF: 0.00179 AC: 71 AN: 39696

South Asian (SAS) AF: 0.0770 AC: 6641 AN: 86212

European-Finnish (FIN) AF: 0.0000568 AC: 3 AN: 52820

Middle Eastern (MID) AF: 0.00920 AC: 53 AN: 5758

European-Non Finnish (NFE) AF: 0.000335 AC: 372 AN: 1110164

Other (OTH) AF: 0.0106 AC: 639 AN: 60334

GnomAD4 genome AF: 0.0200 AC: 3050 AN: 152232 Hom.: 98 Cov.: 32 AF XY: 0.0206 AC XY: 1530 AN XY: 74432

African (AFR) AF: 0.0589 AC: 2445 AN: 41536

American (AMR) AF: 0.00568 AC: 87 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00581 AC: 30 AN: 5162

South Asian (SAS) AF: 0.0862 AC: 416 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000368 AC: 25 AN: 67980

Other (OTH) AF: 0.0208 AC: 44 AN: 2114

Alfa AF: 0.000344 Hom.: 8

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.87
Mutation Taster		=100/0	polymorphism (auto)

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;