chr21-46126476-T-TGGCCCGGCCCGGCCCGGCCC

Variant names:

• chr21-46126476-T-TGGCCCGGCCCGGCCCGGCCC
• rs138363207
• NM_001849.4:c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCC

Variant summary

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

The NM_001849.4(COL6A2):​c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00878 in 1,610,762 control chromosomes in the GnomAD database, including 91 homozygotes. 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. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0091 (85 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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, 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 21-46126476-T-TGGCCCGGCCCGGCCCGGCCC is Benign according to our data. Variant chr21-46126476-T-TGGCCCGGCCCGGCCCGGCCC is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 420369.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 = 0.00566 (862/152234) while in subpopulation NFE AF = 0.01 (680/67976). AF 95% confidence interval is 0.00938. There are 6 homozygotes in GnomAd4. There are 398 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCC		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCC		intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.2423-18_2423-17insCGGCCCGGCCCGGCCCGGCC		intron	N/A	NP_478055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2423-27_2423-26insGGCCCGGCCCGGCCCGGCCC		intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2423-27_2423-26insGGCCCGGCCCGGCCCGGCCC		intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000409416.6	TSL:5	c.2423-27_2423-26insGGCCCGGCCCGGCCCGGCCC		intron	N/A	ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.00567 AC: 862 AN: 152116 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00188

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00259

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00423

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0100

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.00910 AC: 13274 AN: 1458528 Hom.: 85 Cov.: 34 AF XY: 0.00876 AC XY: 6358 AN XY: 725706

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

African (AFR) AF: 0.00158 AC: 53 AN: 33474

American (AMR) AF: 0.00206 AC: 92 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00406 AC: 106 AN: 26120

East Asian (EAS) AF: 0.0000756 AC: 3 AN: 39696

South Asian (SAS) AF: 0.000545 AC: 47 AN: 86216

European-Finnish (FIN) AF: 0.00362 AC: 191 AN: 52808

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5758

European-Non Finnish (NFE) AF: 0.0111 AC: 12346 AN: 1109434

Other (OTH) AF: 0.00705 AC: 425 AN: 60318

⚠️ 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: 0.00566 AC: 862 AN: 152234 Hom.: 6 Cov.: 32 AF XY: 0.00535 AC XY: 398 AN XY: 74434

African (AFR) AF: 0.00188 AC: 78 AN: 41540

American (AMR) AF: 0.00216 AC: 33 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00259 AC: 9 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.000621 AC: 3 AN: 4828

European-Finnish (FIN) AF: 0.00423 AC: 45 AN: 10632

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0100 AC: 680 AN: 67976

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.00151 Hom.: 8

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

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

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; COSMIC: COSV56003846; COSMIC: COSV56003846;