rs2276101

Variant names:

• chr21-46125432-C-T
• rs2276101
• NM_001849.4:c.1817-33C>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.1817-33C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.052 in 1,611,024 control chromosomes in the GnomAD database, including 5,659 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.066 (616 hom., cov: 33)
  • Exomes 𝑓: 0.050 (5043 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.74
• 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: AR, AD, SD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 (MetaRNN=0.004430741).
• BP6: Variant 21-46125432-C-T is Benign according to our data. Variant chr21-46125432-C-T is described in ClinVar as Benign. ClinVar VariationId is 93924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.334 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.1817-33C>T		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1817-33C>T		intron	N/A	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1817-33C>T		intron	N/A	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1817-33C>T		intron	N/A	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1817-33C>T		intron	N/A	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000413758.1	TSL:3	c.455C>T	p.Pro152Leu	missense	Exon 10 of 11	ENSP00000395751.1	H7C0M5

Frequencies

GnomAD3 genomes AF: 0.0663 AC: 10059 AN: 151834 Hom.: 614 Cov.: 33

Gnomad AFR AF: 0.0858

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0760

Gnomad ASJ AF: 0.0401

Gnomad EAS AF: 0.348

Gnomad SAS AF: 0.0925

Gnomad FIN AF: 0.0252

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0361

Gnomad OTH AF: 0.0824

GnomAD2 exomes AF: 0.0753 AC: 18789 AN: 249494 AF XY: 0.0724

Gnomad AFR exome AF: 0.0908

Gnomad AMR exome AF: 0.0896

Gnomad ASJ exome AF: 0.0347

Gnomad EAS exome AF: 0.339

Gnomad FIN exome AF: 0.0257

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0577

GnomAD4 exome AF: 0.0505 AC: 73631 AN: 1459070 Hom.: 5043 Cov.: 37 AF XY: 0.0512 AC XY: 37190 AN XY: 725804

African (AFR) AF: 0.0864 AC: 2888 AN: 33438

American (AMR) AF: 0.0894 AC: 3994 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.0368 AC: 961 AN: 26090

East Asian (EAS) AF: 0.408 AC: 16200 AN: 39668

South Asian (SAS) AF: 0.0788 AC: 6792 AN: 86188

European-Finnish (FIN) AF: 0.0253 AC: 1317 AN: 52150

Middle Eastern (MID) AF: 0.0732 AC: 422 AN: 5766

European-Non Finnish (NFE) AF: 0.0338 AC: 37491 AN: 1110782

Other (OTH) AF: 0.0591 AC: 3566 AN: 60298

GnomAD4 genome AF: 0.0662 AC: 10063 AN: 151954 Hom.: 616 Cov.: 33 AF XY: 0.0682 AC XY: 5066 AN XY: 74304

African (AFR) AF: 0.0856 AC: 3553 AN: 41514

American (AMR) AF: 0.0759 AC: 1160 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0401 AC: 139 AN: 3466

East Asian (EAS) AF: 0.348 AC: 1788 AN: 5142

South Asian (SAS) AF: 0.0924 AC: 445 AN: 4818

European-Finnish (FIN) AF: 0.0252 AC: 267 AN: 10614

Middle Eastern (MID) AF: 0.0748 AC: 22 AN: 294

European-Non Finnish (NFE) AF: 0.0361 AC: 2447 AN: 67798

Other (OTH) AF: 0.0839 AC: 177 AN: 2110

Alfa AF: 0.0453 Hom.: 78

Bravo AF: 0.0731

Asia WGS AF: 0.169 AC: 587 AN: 3478

EpiCase AF: 0.0412

EpiControl AF: 0.0389

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	0.057
DANN	Benign	0.68
DEOGEN2	Benign	0.030	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0054	N
LIST_S2	Benign	0.29	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.0	T
PhyloP100		-3.7
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.096
Sift	Benign	0.13	T
Sift4G	Benign	0.13	T
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2276101;

hg19: chr21-47545346;

COSMIC: COSV56014201;