rs114284669

Variant names:

• chr2-237376802-T-C
• rs114284669
• NM_004369.4:c.3040A>G

Your query was ambiguous. Multiple possible variants found:

• chr2-237376802-T-C
• chr2-237376802-T-G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS1

The NM_004369.4(COL6A3):​c.3040A>G​(p.Lys1014Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000371 in 1,614,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1014Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:3
• Conservation: PhyloP100: 2.80
• Publications: 8 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

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

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• dystonia 27

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Ambry Genetics, Illumina
• Ullrich congenital muscular dystrophy 1A

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.32305047).
• BP6: Variant 2-237376802-T-C is Benign according to our data. Variant chr2-237376802-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 162547.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000263 (40/152312) while in subpopulation NFE AF = 0.0005 (34/68030). AF 95% confidence interval is 0.000368. There are 0 homozygotes in GnomAd4. There are 15 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

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.3040A>G	p.Lys1014Glu	missense	Exon 7 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.2422A>G	p.Lys808Glu	missense	Exon 6 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.1219A>G	p.Lys407Glu	missense	Exon 4 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.3040A>G	p.Lys1014Glu	missense	Exon 7 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.1219A>G	p.Lys407Glu	missense	Exon 4 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000392004.7	TSL:1	c.2422A>G	p.Lys808Glu	missense	Exon 6 of 8	ENSP00000375861.3	P12111-5

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000215 AC: 54 AN: 251224 AF XY: 0.000265

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000414

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000382 AC: 559 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000375 AC XY: 273 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.000134 AC: 6 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000482 AC: 536 AN: 1112012

Other (OTH) AF: 0.000265 AC: 16 AN: 60396

GnomAD4 genome AF: 0.000263 AC: 40 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74492

African (AFR) AF: 0.0000962 AC: 4 AN: 41568

American (AMR) AF: 0.0000654 AC: 1 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000360 Hom.: 0

Bravo AF: 0.000264

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.000600

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	1	-	Dystonia 27 (1)
-	-	1	not specified (1)
-	1	-	Ullrich congenital muscular dystrophy 1A;C4225336:Dystonia 27;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Pathogenic	0.19
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.16
Eigen_PC	Benign	0.089
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.88	D
M_CAP	Uncertain	0.19	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.086	D
MutationAssessor	Uncertain	2.6	M
PhyloP100		2.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.5	N
REVEL	Uncertain	0.60
Sift	Benign	0.12	T
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.59
MVP		0.85
MPC		0.48
ClinPred		0.14	T
GERP RS		5.5
Varity_R		0.19
gMVP		0.48
Mutation Taster		=2/98	disease causing

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: rs114284669; hg19: chr2-238285445;