rs55933135

Variant names:

• chr21-46124748-A-G
• rs55933135
• NM_001849.4:c.1734+35A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.1734+35A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,607,886 control chromosomes in the GnomAD database, including 11,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2487 hom., cov: 33)
  • Exomes 𝑓: 0.098 (8638 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.10
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BP6: Variant 21-46124748-A-G is Benign according to our data. Variant chr21-46124748-A-G is described in ClinVar as Benign. ClinVar VariationId is 93918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.313 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.1734+35A>G		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1734+35A>G		intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.1734+35A>G		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.1734+35A>G		intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1734+35A>G		intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000409416.6	TSL:5	c.1734+35A>G		intron	N/A	ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.147 AC: 22312 AN: 151794 Hom.: 2475 Cov.: 33

Gnomad AFR AF: 0.318

Gnomad AMI AF: 0.0684

Gnomad AMR AF: 0.0777

Gnomad ASJ AF: 0.0784

Gnomad EAS AF: 0.0254

Gnomad SAS AF: 0.153

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.0916

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.0964 AC: 23861 AN: 247630 AF XY: 0.0968

Gnomad AFR exome AF: 0.324

Gnomad AMR exome AF: 0.0510

Gnomad ASJ exome AF: 0.0790

Gnomad EAS exome AF: 0.0266

Gnomad FIN exome AF: 0.0266

Gnomad NFE exome AF: 0.0906

Gnomad OTH exome AF: 0.0838

GnomAD4 exome AF: 0.0982 AC: 142914 AN: 1455970 Hom.: 8638 Cov.: 33 AF XY: 0.0987 AC XY: 71510 AN XY: 724474

African (AFR) AF: 0.332 AC: 11078 AN: 33362

American (AMR) AF: 0.0553 AC: 2469 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 2113 AN: 26076

East Asian (EAS) AF: 0.0226 AC: 895 AN: 39678

South Asian (SAS) AF: 0.143 AC: 12348 AN: 86102

European-Finnish (FIN) AF: 0.0291 AC: 1516 AN: 52138

Middle Eastern (MID) AF: 0.135 AC: 776 AN: 5754

European-Non Finnish (NFE) AF: 0.0952 AC: 105443 AN: 1108088

Other (OTH) AF: 0.104 AC: 6276 AN: 60156

GnomAD4 genome AF: 0.147 AC: 22364 AN: 151916 Hom.: 2487 Cov.: 33 AF XY: 0.142 AC XY: 10528 AN XY: 74256

African (AFR) AF: 0.318 AC: 13149 AN: 41374

American (AMR) AF: 0.0775 AC: 1184 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0784 AC: 272 AN: 3468

East Asian (EAS) AF: 0.0254 AC: 131 AN: 5156

South Asian (SAS) AF: 0.153 AC: 734 AN: 4810

European-Finnish (FIN) AF: 0.0271 AC: 287 AN: 10586

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.0916 AC: 6226 AN: 67936

Other (OTH) AF: 0.134 AC: 282 AN: 2106

Alfa AF: 0.117 Hom.: 292

Bravo AF: 0.157

Asia WGS AF: 0.134 AC: 469 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.41
DANN	Benign	0.24
PhyloP100		-3.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs55933135; hg19: chr21-47544662;