rs16978878

Variant names:

• chr21-46126468-C-A
• rs16978878
• NM_001849.4:c.2423-35C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46126468-C-A
• chr21-46126468-C-G
• chr21-46126468-C-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.2423-35C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.089 in 1,608,332 control chromosomes in the GnomAD database, including 7,234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.078 (493 hom., cov: 33)
  • Exomes 𝑓: 0.090 (6741 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.468
• Publications: 6 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=-0.85).
• BP6: Variant 21-46126468-C-A is Benign according to our data. Variant chr21-46126468-C-A is described in ClinVar as Benign. ClinVar VariationId is 93939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.145 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.2423-35C>A		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.2423-35C>A		intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.2423-35C>A		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.2423-35C>A		intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2423-35C>A		intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000409416.6	TSL:5	c.2423-35C>A		intron	N/A	ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0777 AC: 11817 AN: 152060 Hom.: 491 Cov.: 33

Gnomad AFR AF: 0.0768

Gnomad AMI AF: 0.0672

Gnomad AMR AF: 0.0500

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.154

Gnomad FIN AF: 0.0271

Gnomad MID AF: 0.130

Gnomad NFE AF: 0.0909

Gnomad OTH AF: 0.0809

GnomAD2 exomes AF: 0.0736 AC: 18264 AN: 248244 AF XY: 0.0791

Gnomad AFR exome AF: 0.0759

Gnomad AMR exome AF: 0.0374

Gnomad ASJ exome AF: 0.0752

Gnomad EAS exome AF: 0.0239

Gnomad FIN exome AF: 0.0251

Gnomad NFE exome AF: 0.0816

Gnomad OTH exome AF: 0.0743

GnomAD4 exome AF: 0.0901 AC: 131232 AN: 1456154 Hom.: 6741 Cov.: 33 AF XY: 0.0917 AC XY: 66468 AN XY: 724626

African (AFR) AF: 0.0808 AC: 2705 AN: 33462

American (AMR) AF: 0.0415 AC: 1856 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0801 AC: 2089 AN: 26092

East Asian (EAS) AF: 0.0229 AC: 909 AN: 39686

South Asian (SAS) AF: 0.143 AC: 12286 AN: 86162

European-Finnish (FIN) AF: 0.0285 AC: 1503 AN: 52756

Middle Eastern (MID) AF: 0.123 AC: 707 AN: 5750

European-Non Finnish (NFE) AF: 0.0938 AC: 103820 AN: 1107340

Other (OTH) AF: 0.0889 AC: 5357 AN: 60230

GnomAD4 genome AF: 0.0777 AC: 11830 AN: 152178 Hom.: 493 Cov.: 33 AF XY: 0.0749 AC XY: 5573 AN XY: 74398

African (AFR) AF: 0.0768 AC: 3189 AN: 41536

American (AMR) AF: 0.0500 AC: 765 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3470

East Asian (EAS) AF: 0.0242 AC: 125 AN: 5164

South Asian (SAS) AF: 0.154 AC: 743 AN: 4822

European-Finnish (FIN) AF: 0.0271 AC: 288 AN: 10622

Middle Eastern (MID) AF: 0.116 AC: 34 AN: 294

European-Non Finnish (NFE) AF: 0.0909 AC: 6175 AN: 67944

Other (OTH) AF: 0.0853 AC: 180 AN: 2110

Alfa AF: 0.0434 Hom.: 48

Bravo AF: 0.0780

Asia WGS AF: 0.121 AC: 422 AN: 3476

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.85
PhyloP100		-0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs16978878; hg19: chr21-47546382;