rs1077182

Variant names:

• chr21-46121639-A-G
• rs1077182
• NM_001849.4:c.1521+21A>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.1521+21A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.163 in 1,611,126 control chromosomes in the GnomAD database, including 24,307 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1376 hom., cov: 33)
  • Exomes 𝑓: 0.17 (22931 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.648
• Publications: 7 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=-0.87).
• BP6: Variant 21-46121639-A-G is Benign according to our data. Variant chr21-46121639-A-G is described in ClinVar as Benign. ClinVar VariationId is 93908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.18 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1521+21A>G		intron_variant	Intron 18 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1521+21A>G		intron_variant	Intron 18 of 27		NP_478054.2
COL6A2	NM_058175.3	c.1521+21A>G		intron_variant	Intron 18 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1521+21A>G		intron_variant	Intron 18 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1521+21A>G		intron_variant	Intron 18 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1521+21A>G		intron_variant	Intron 17 of 26	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.144+21A>G		intron_variant	Intron 3 of 10	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.118 AC: 17937 AN: 152088 Hom.: 1377 Cov.: 33

Gnomad AFR AF: 0.0496

Gnomad AMI AF: 0.0746

Gnomad AMR AF: 0.0932

Gnomad ASJ AF: 0.155

Gnomad EAS AF: 0.0197

Gnomad SAS AF: 0.0743

Gnomad FIN AF: 0.0612

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.183

Gnomad OTH AF: 0.130

GnomAD2 exomes AF: 0.120 AC: 29797 AN: 247474 AF XY: 0.124

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.0691

Gnomad ASJ exome AF: 0.157

Gnomad EAS exome AF: 0.0245

Gnomad FIN exome AF: 0.0625

Gnomad NFE exome AF: 0.181

Gnomad OTH exome AF: 0.140

GnomAD4 exome AF: 0.168 AC: 244629 AN: 1458920 Hom.: 22931 Cov.: 33 AF XY: 0.165 AC XY: 119876 AN XY: 725834

African (AFR) AF: 0.0432 AC: 1445 AN: 33468

American (AMR) AF: 0.0731 AC: 3269 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.161 AC: 4203 AN: 26120

East Asian (EAS) AF: 0.0224 AC: 891 AN: 39690

South Asian (SAS) AF: 0.0777 AC: 6699 AN: 86226

European-Finnish (FIN) AF: 0.0680 AC: 3540 AN: 52076

Middle Eastern (MID) AF: 0.155 AC: 894 AN: 5756

European-Non Finnish (NFE) AF: 0.193 AC: 214249 AN: 1110590

Other (OTH) AF: 0.157 AC: 9439 AN: 60296

GnomAD4 genome AF: 0.118 AC: 17941 AN: 152206 Hom.: 1376 Cov.: 33 AF XY: 0.111 AC XY: 8269 AN XY: 74396

African (AFR) AF: 0.0497 AC: 2066 AN: 41550

American (AMR) AF: 0.0932 AC: 1425 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.155 AC: 537 AN: 3470

East Asian (EAS) AF: 0.0198 AC: 102 AN: 5164

South Asian (SAS) AF: 0.0737 AC: 356 AN: 4828

European-Finnish (FIN) AF: 0.0612 AC: 649 AN: 10606

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.183 AC: 12430 AN: 67972

Other (OTH) AF: 0.129 AC: 272 AN: 2116

Alfa AF: 0.151 Hom.: 379

Bravo AF: 0.118

Asia WGS AF: 0.0650 AC: 228 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

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.5
DANN	Benign	0.56
PhyloP100		0.65
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: rs1077182; hg19: chr21-47541553;