21-46119151-C-T

Variant names:

• chr21-46119151-C-T
• rs76825716
• NM_001849.4:c.1269+32C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.1269+32C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0166 in 1,521,670 control chromosomes in the GnomAD database, including 262 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (45 hom., cov: 34)
  • Exomes 𝑓: 0.016 (217 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.16
• Publications: 1 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=-0.9).
• BP6: Variant 21-46119151-C-T is Benign according to our data. Variant chr21-46119151-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 258315.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0193 (2941/152276) while in subpopulation AFR AF = 0.0303 (1258/41562). AF 95% confidence interval is 0.0289. There are 45 homozygotes in GnomAd4. There are 1360 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 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.1269+32C>T		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1269+32C>T		intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.1269+32C>T		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.1269+32C>T		intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1269+32C>T		intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000409416.6	TSL:5	c.1269+32C>T		intron	N/A	ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0193 AC: 2937 AN: 152160 Hom.: 45 Cov.: 34

Gnomad AFR AF: 0.0302

Gnomad AMI AF: 0.0175

Gnomad AMR AF: 0.0218

Gnomad ASJ AF: 0.00980

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00310

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0172

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0143 AC: 3130 AN: 218882 AF XY: 0.0139

Gnomad AFR exome AF: 0.0316

Gnomad AMR exome AF: 0.0190

Gnomad ASJ exome AF: 0.0125

Gnomad EAS exome AF: 0.000124

Gnomad FIN exome AF: 0.00383

Gnomad NFE exome AF: 0.0172

Gnomad OTH exome AF: 0.0202

GnomAD4 exome AF: 0.0163 AC: 22254 AN: 1369394 Hom.: 217 Cov.: 23 AF XY: 0.0159 AC XY: 10906 AN XY: 684858

African (AFR) AF: 0.0281 AC: 890 AN: 31696

American (AMR) AF: 0.0191 AC: 812 AN: 42464

Ashkenazi Jewish (ASJ) AF: 0.0124 AC: 313 AN: 25316

East Asian (EAS) AF: 0.000155 AC: 6 AN: 38630

South Asian (SAS) AF: 0.00623 AC: 518 AN: 83160

European-Finnish (FIN) AF: 0.00458 AC: 234 AN: 51074

Middle Eastern (MID) AF: 0.0234 AC: 107 AN: 4572

European-Non Finnish (NFE) AF: 0.0178 AC: 18416 AN: 1035278

Other (OTH) AF: 0.0167 AC: 958 AN: 57204

GnomAD4 genome AF: 0.0193 AC: 2941 AN: 152276 Hom.: 45 Cov.: 34 AF XY: 0.0183 AC XY: 1360 AN XY: 74452

African (AFR) AF: 0.0303 AC: 1258 AN: 41562

American (AMR) AF: 0.0218 AC: 333 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00980 AC: 34 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00539 AC: 26 AN: 4826

European-Finnish (FIN) AF: 0.00310 AC: 33 AN: 10630

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0172 AC: 1168 AN: 67998

Other (OTH) AF: 0.0294 AC: 62 AN: 2112

Alfa AF: 0.00812 Hom.: 0

Bravo AF: 0.0209

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 03, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	1.5
DANN	Benign	0.71
PhyloP100		-1.2
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: rs76825716; hg19: chr21-47539065; COSMIC: COSV56011608; COSMIC: COSV56011608;