chr21-46126476-T-TGGCCCGGCCCGGCCC

Variant names:

• chr21-46126476-T-TGGCCCGGCCCGGCCC
• rs138363207
• NM_001849.4:c.2423-18_2423-17insCGGCCCGGCCCGGCC

Variant summary

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

The NM_001849.4(COL6A2):​c.2423-18_2423-17insCGGCCCGGCCCGGCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.051 in 152,210 control chromosomes in the GnomAD database, including 265 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 0.051 (265 hom., cov: 32)
  • Exomes 𝑓: 0.073 (4488 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Likely 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, 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 -10 ACMG points.

• BP6: Variant 21-46126476-T-TGGCCCGGCCCGGCCC is Benign according to our data. Variant chr21-46126476-T-TGGCCCGGCCCGGCCC is described in ClinVar as [Likely_benign]. Clinvar id is 258324.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.2423-18_2423-17insCGGCCCGGCCCGGCC		intron_variant	Intron 26 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.2423-18_2423-17insCGGCCCGGCCCGGCC		intron_variant	Intron 26 of 27		NP_478054.2
COL6A2	NM_058175.3	c.2423-18_2423-17insCGGCCCGGCCCGGCC		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_2423-26insGGCCCGGCCCGGCCC		intron_variant	Intron 26 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.2423-27_2423-26insGGCCCGGCCCGGCCC		intron_variant	Intron 26 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.2423-27_2423-26insGGCCCGGCCCGGCCC		intron_variant	Intron 25 of 26	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0511 AC: 7773 AN: 152092 Hom.: 267 Cov.: 32

Gnomad AFR AF: 0.0151

Gnomad AMI AF: 0.0670

Gnomad AMR AF: 0.0420

Gnomad ASJ AF: 0.0753

Gnomad EAS AF: 0.0185

Gnomad SAS AF: 0.0607

Gnomad FIN AF: 0.0226

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.0793

Gnomad OTH AF: 0.0593

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0731 AC: 106489 AN: 1457208 Hom.: 4488 Cov.: 34 AF XY: 0.0730 AC XY: 52954 AN XY: 725056

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

African (AFR) AF: 0.0137 AC: 457 AN: 33468

American (AMR) AF: 0.0356 AC: 1591 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.0754 AC: 1968 AN: 26104

East Asian (EAS) AF: 0.0211 AC: 836 AN: 39690

South Asian (SAS) AF: 0.0618 AC: 5323 AN: 86168

European-Finnish (FIN) AF: 0.0245 AC: 1293 AN: 52780

Middle Eastern (MID) AF: 0.112 AC: 642 AN: 5754

European-Non Finnish (NFE) AF: 0.0813 AC: 90136 AN: 1108310

Other (OTH) AF: 0.0704 AC: 4243 AN: 60250

⚠️ 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 AF: 0.0510 AC: 7765 AN: 152210 Hom.: 265 Cov.: 32 AF XY: 0.0479 AC XY: 3567 AN XY: 74420

African (AFR) AF: 0.0151 AC: 628 AN: 41534

American (AMR) AF: 0.0420 AC: 642 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0753 AC: 261 AN: 3468

East Asian (EAS) AF: 0.0186 AC: 96 AN: 5164

South Asian (SAS) AF: 0.0605 AC: 292 AN: 4826

European-Finnish (FIN) AF: 0.0226 AC: 240 AN: 10630

Middle Eastern (MID) AF: 0.102 AC: 30 AN: 294

European-Non Finnish (NFE) AF: 0.0793 AC: 5392 AN: 67970

Other (OTH) AF: 0.0582 AC: 123 AN: 2114

Alfa AF: 0.0134 Hom.: 8

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Apr 15, 2016

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

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;