rs9976026

Variant names:

• chr21-46122072-T-C
• rs9976026
• NM_001849.4:c.1522-36T>C

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.1522-36T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.164 in 1,609,124 control chromosomes in the GnomAD database, including 24,245 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1411 hom., cov: 32)
  • Exomes 𝑓: 0.17 (22834 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.847
• Publications: 3 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=-0.86).
• BP6: Variant 21-46122072-T-C is Benign according to our data. Variant chr21-46122072-T-C is described in ClinVar as Benign. ClinVar VariationId is 93910.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.1522-36T>C		intron_variant	Intron 18 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1522-36T>C		intron_variant	Intron 18 of 27	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1522-36T>C		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.1522-36T>C		intron_variant	Intron 18 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1522-36T>C		intron_variant	Intron 18 of 27	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1522-36T>C		intron_variant	Intron 17 of 26	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.145-36T>C		intron_variant	Intron 3 of 10	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.122 AC: 18539 AN: 151970 Hom.: 1413 Cov.: 32

Gnomad AFR AF: 0.0657

Gnomad AMI AF: 0.0749

Gnomad AMR AF: 0.0949

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0195

Gnomad SAS AF: 0.0746

Gnomad FIN AF: 0.0613

Gnomad MID AF: 0.140

Gnomad NFE AF: 0.182

Gnomad OTH AF: 0.133

GnomAD2 exomes AF: 0.120 AC: 29642 AN: 246176 AF XY: 0.124

Gnomad AFR exome AF: 0.0649

Gnomad AMR exome AF: 0.0700

Gnomad ASJ exome AF: 0.134

Gnomad EAS exome AF: 0.0244

Gnomad FIN exome AF: 0.0616

Gnomad NFE exome AF: 0.180

Gnomad OTH exome AF: 0.137

GnomAD4 exome AF: 0.168 AC: 244626 AN: 1457036 Hom.: 22834 Cov.: 32 AF XY: 0.165 AC XY: 119820 AN XY: 724920

African (AFR) AF: 0.0588 AC: 1966 AN: 33440

American (AMR) AF: 0.0741 AC: 3305 AN: 44624

Ashkenazi Jewish (ASJ) AF: 0.139 AC: 3621 AN: 26086

East Asian (EAS) AF: 0.0225 AC: 891 AN: 39676

South Asian (SAS) AF: 0.0783 AC: 6737 AN: 86014

European-Finnish (FIN) AF: 0.0677 AC: 3523 AN: 52002

Middle Eastern (MID) AF: 0.153 AC: 882 AN: 5754

European-Non Finnish (NFE) AF: 0.193 AC: 214309 AN: 1109190

Other (OTH) AF: 0.156 AC: 9392 AN: 60250

GnomAD4 genome AF: 0.122 AC: 18546 AN: 152088 Hom.: 1411 Cov.: 32 AF XY: 0.115 AC XY: 8546 AN XY: 74348

African (AFR) AF: 0.0659 AC: 2735 AN: 41492

American (AMR) AF: 0.0948 AC: 1449 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 470 AN: 3472

East Asian (EAS) AF: 0.0196 AC: 101 AN: 5156

South Asian (SAS) AF: 0.0741 AC: 356 AN: 4806

European-Finnish (FIN) AF: 0.0613 AC: 650 AN: 10610

Middle Eastern (MID) AF: 0.123 AC: 36 AN: 292

European-Non Finnish (NFE) AF: 0.183 AC: 12404 AN: 67952

Other (OTH) AF: 0.131 AC: 277 AN: 2116

Alfa AF: 0.150 Hom.: 491

Bravo AF: 0.123

Asia WGS AF: 0.0660 AC: 229 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Nov 16, 2012

Eurofins Ntd Llc (ga)

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.48
DANN	Benign	0.68
PhyloP100		-0.85
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: rs9976026; hg19: chr21-47541986;