rs11896521

Variant names:

• chr2-237374829-T-G
• rs11896521
• NM_004369.4:c.3262A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.3262A>C​(p.Lys1088Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0167 in 1,613,924 control chromosomes in the GnomAD database, including 1,501 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1088E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.055 (569 hom., cov: 32)
  • Exomes 𝑓: 0.013 (932 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 3.12
• Publications: 15 publications found

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AD, SD, AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, SD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1C

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, SD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Illumina, Ambry Genetics, ClinGen, Orphanet
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0013917685).
• BP6: Variant 2-237374829-T-G is Benign according to our data. Variant chr2-237374829-T-G is described in ClinVar as Benign. ClinVar VariationId is 94924.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.149 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004369.4. 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
	COL6A3	NM_004369.4	MANE Select	c.3262A>C	p.Lys1088Gln	missense	Exon 8 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.2644A>C	p.Lys882Gln	missense	Exon 7 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.1441A>C	p.Lys481Gln	missense	Exon 5 of 41	NP_476507.3	P12111-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.3262A>C	p.Lys1088Gln	missense	Exon 8 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.1441A>C	p.Lys481Gln	missense	Exon 5 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000392004.7	TSL:1	c.2644A>C	p.Lys882Gln	missense	Exon 7 of 8	ENSP00000375861.3	P12111-5

Frequencies

GnomAD3 genomes AF: 0.0550 AC: 8364 AN: 151942 Hom.: 567 Cov.: 32

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0740

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.0340

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00128

Gnomad OTH AF: 0.0408

GnomAD2 exomes AF: 0.0374 AC: 9392 AN: 251150 AF XY: 0.0318

Gnomad AFR exome AF: 0.149

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0433

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.0238

GnomAD4 exome AF: 0.0127 AC: 18533 AN: 1461864 Hom.: 932 Cov.: 32 AF XY: 0.0124 AC XY: 9018 AN XY: 727234

African (AFR) AF: 0.149 AC: 5001 AN: 33480

American (AMR) AF: 0.114 AC: 5115 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0487 AC: 1934 AN: 39700

South Asian (SAS) AF: 0.0321 AC: 2766 AN: 86254

European-Finnish (FIN) AF: 0.0266 AC: 1419 AN: 53398

Middle Eastern (MID) AF: 0.00780 AC: 45 AN: 5768

European-Non Finnish (NFE) AF: 0.000933 AC: 1037 AN: 1112012

Other (OTH) AF: 0.0196 AC: 1184 AN: 60392

GnomAD4 genome AF: 0.0551 AC: 8381 AN: 152060 Hom.: 569 Cov.: 32 AF XY: 0.0568 AC XY: 4224 AN XY: 74322

African (AFR) AF: 0.152 AC: 6316 AN: 41460

American (AMR) AF: 0.0742 AC: 1134 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0451 AC: 232 AN: 5146

South Asian (SAS) AF: 0.0341 AC: 164 AN: 4816

European-Finnish (FIN) AF: 0.0340 AC: 359 AN: 10574

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00128 AC: 87 AN: 67998

Other (OTH) AF: 0.0404 AC: 85 AN: 2104

Alfa AF: 0.0202 Hom.: 534

Bravo AF: 0.0621

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.138 AC: 610

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.0360 AC: 4377

Asia WGS AF: 0.0620 AC: 216 AN: 3478

EpiCase AF: 0.00115

EpiControl AF: 0.000652

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	18
DANN	Benign	0.88
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.26
FATHMM_MKL	Benign	0.75	D
LIST_S2	Benign	0.45	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-0.84	T
MutationAssessor	Benign	1.2	L
PhyloP100		3.1
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.25	N
REVEL	Uncertain	0.30
Sift	Benign	1.0	T
Sift4G	Benign	0.73	T
Polyphen		0.34	B
Vest4		0.050
MPC		0.26
ClinPred		0.038	T
GERP RS		4.4
Varity_R		0.12
gMVP		0.69
Mutation Taster		=90/10	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs11896521; hg19: chr2-238283472; COSMIC: COSV55094196; COSMIC: COSV55094196;