2-237366926-T-C

Variant names:

• chr2-237366926-T-C
• rs77632596
• NM_004369.4:c.5261A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004369.4(COL6A3):​c.5261A>G​(p.Lys1754Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00868 in 1,614,222 control chromosomes in the GnomAD database, including 80 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. K1754M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0079 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0088 (63 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 0.293
• Publications: 11 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008732289).
• BP6: Variant 2-237366926-T-C is Benign according to our data. Variant chr2-237366926-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94945.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0079 (1203/152336) while in subpopulation AMR AF = 0.00987 (151/15300). AF 95% confidence interval is 0.00896. There are 17 homozygotes in GnomAd4. There are 616 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD,SD gene

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.5261A>G	p.Lys1754Arg	missense	Exon 11 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.4643A>G	p.Lys1548Arg	missense	Exon 10 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.3440A>G	p.Lys1147Arg	missense	Exon 8 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.5261A>G	p.Lys1754Arg	missense	Exon 11 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.3440A>G	p.Lys1147Arg	missense	Exon 8 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.4643A>G	p.Lys1548Arg	missense	Exon 10 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.00791 AC: 1204 AN: 152218 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.00988

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00270

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00957

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00775 AC: 1949 AN: 251478 AF XY: 0.00784

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0149

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0108

Gnomad OTH exome AF: 0.00994

GnomAD4 exome AF: 0.00876 AC: 12802 AN: 1461886 Hom.: 63 Cov.: 32 AF XY: 0.00858 AC XY: 6240 AN XY: 727242

African (AFR) AF: 0.00179 AC: 60 AN: 33480

American (AMR) AF: 0.00528 AC: 236 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 419 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.00180 AC: 155 AN: 86258

European-Finnish (FIN) AF: 0.0116 AC: 618 AN: 53420

Middle Eastern (MID) AF: 0.0133 AC: 77 AN: 5768

European-Non Finnish (NFE) AF: 0.00964 AC: 10717 AN: 1112004

Other (OTH) AF: 0.00859 AC: 519 AN: 60396

GnomAD4 genome AF: 0.00790 AC: 1203 AN: 152336 Hom.: 17 Cov.: 33 AF XY: 0.00827 AC XY: 616 AN XY: 74500

African (AFR) AF: 0.00233 AC: 97 AN: 41578

American (AMR) AF: 0.00987 AC: 151 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0164 AC: 57 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00270 AC: 13 AN: 4818

European-Finnish (FIN) AF: 0.0126 AC: 134 AN: 10626

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00957 AC: 651 AN: 68032

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00925 Hom.: 16

Bravo AF: 0.00760

TwinsUK AF: 0.0102 AC: 38

ALSPAC AF: 0.0119 AC: 46

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.00930 AC: 80

ExAC AF: 0.00775 AC: 941

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	5	not provided (5)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	15
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Benign	-0.51
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0087	T
MetaSVM	Benign	-0.75	T
MutationAssessor	Benign	0.17	N
PhyloP100		0.29
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.23
Sift	Benign	0.22	T
Sift4G	Benign	0.37	T
Polyphen		0.78	P
Vest4		0.20
MVP		0.77
MPC		0.18
ClinPred		0.0035	T
GERP RS		1.8
Varity_R		0.16
gMVP		0.53
Mutation Taster		=97/3	polymorphism

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: rs77632596; hg19: chr2-238275569; COSMIC: COSV107337113; COSMIC: COSV107337113;