chr21-46131919-C-T

Variant names:

• chr21-46131919-C-T
• rs7279622
• NM_001849.4:c.2462-35C>T

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.2462-35C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.554 in 1,547,548 control chromosomes in the GnomAD database, including 240,733 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.54 (22538 hom., cov: 34)
  • Exomes 𝑓: 0.56 (218195 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.42
• Publications: 8 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=-0.78).
• BP6: Variant 21-46131919-C-T is Benign according to our data. Variant chr21-46131919-C-T is described in ClinVar as Benign. ClinVar VariationId is 93940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.65 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.2462-35C>T		intron	N/A	NP_001840.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2462-35C>T		intron	N/A	ENSP00000300527.4

Frequencies

GnomAD3 genomes AF: 0.537 AC: 81616 AN: 151976 Hom.: 22513 Cov.: 34

Gnomad AFR AF: 0.424

Gnomad AMI AF: 0.684

Gnomad AMR AF: 0.660

Gnomad ASJ AF: 0.577

Gnomad EAS AF: 0.501

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.638

Gnomad MID AF: 0.475

Gnomad NFE AF: 0.574

Gnomad OTH AF: 0.550

GnomAD2 exomes AF: 0.553 AC: 86242 AN: 155946 AF XY: 0.536

Gnomad AFR exome AF: 0.408

Gnomad AMR exome AF: 0.719

Gnomad ASJ exome AF: 0.572

Gnomad EAS exome AF: 0.495

Gnomad FIN exome AF: 0.650

Gnomad NFE exome AF: 0.564

Gnomad OTH exome AF: 0.582

GnomAD4 exome AF: 0.555 AC: 774969 AN: 1395454 Hom.: 218195 Cov.: 30 AF XY: 0.549 AC XY: 379567 AN XY: 690778

African (AFR) AF: 0.417 AC: 13234 AN: 31700

American (AMR) AF: 0.713 AC: 26505 AN: 37170

Ashkenazi Jewish (ASJ) AF: 0.575 AC: 14537 AN: 25288

East Asian (EAS) AF: 0.466 AC: 16853 AN: 36156

South Asian (SAS) AF: 0.365 AC: 29261 AN: 80100

European-Finnish (FIN) AF: 0.639 AC: 26899 AN: 42108

Middle Eastern (MID) AF: 0.504 AC: 2410 AN: 4782

European-Non Finnish (NFE) AF: 0.568 AC: 613578 AN: 1080154

Other (OTH) AF: 0.546 AC: 31692 AN: 57996

GnomAD4 genome AF: 0.537 AC: 81687 AN: 152094 Hom.: 22538 Cov.: 34 AF XY: 0.539 AC XY: 40094 AN XY: 74352

African (AFR) AF: 0.425 AC: 17626 AN: 41496

American (AMR) AF: 0.661 AC: 10098 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.577 AC: 2002 AN: 3470

East Asian (EAS) AF: 0.501 AC: 2581 AN: 5150

South Asian (SAS) AF: 0.356 AC: 1717 AN: 4824

European-Finnish (FIN) AF: 0.638 AC: 6753 AN: 10588

Middle Eastern (MID) AF: 0.476 AC: 140 AN: 294

European-Non Finnish (NFE) AF: 0.574 AC: 38992 AN: 67960

Other (OTH) AF: 0.545 AC: 1154 AN: 2116

Alfa AF: 0.558 Hom.: 4380

Bravo AF: 0.539

Asia WGS AF: 0.453 AC: 1573 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Myosclerosis (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.56
DANN	Benign	0.93
PhyloP100		-1.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs7279622; hg19: chr21-47551833; COSMIC: COSV52426489; COSMIC: COSV52426489;