rs116690555

chr2-237352524-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_004369.4(COL6A3):c.6751C>T(p.Arg2251Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000236 in 1,611,808 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. 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. R2251Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: COL6A3 NM_004369.4 missense, splice_region
• Scores: Splicing: ADA: 0.04728
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 3.02

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026623517).
• BP6: Variant 2-237352524-G-A is Benign according to our data. Variant chr2-237352524-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 166939.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=1, Likely_benign=4}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000145 (212/1459534) while in subpopulation AFR AF= 0.00422 (141/33440). AF 95% confidence interval is 0.00365. There are 1 homozygotes in gnomad4_exome. There are 96 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A3	NM_004369.4	c.6751C>T	p.Arg2251Trp	missense_variant, splice_region_variant	26/44	ENST00000295550.9
COL6A3	NM_057167.4	c.6133C>T	p.Arg2045Trp	missense_variant, splice_region_variant	25/43
COL6A3	NM_057166.5	c.4930C>T	p.Arg1644Trp	missense_variant, splice_region_variant	23/41

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A3	ENST00000295550.9	c.6751C>T	p.Arg2251Trp	missense_variant, splice_region_variant	26/44	1	NM_004369.4	P1
COL6A3	ENST00000472056.5	c.4930C>T	p.Arg1644Trp	missense_variant, splice_region_variant	23/41	1
COL6A3	ENST00000353578.9	c.6133C>T	p.Arg2045Trp	missense_variant, splice_region_variant	25/43	5
COL6A3	ENST00000491769.1	n.1005C>T		splice_region_variant, non_coding_transcript_exon_variant	3/20	5

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152156 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00381

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000312 AC: 77 AN: 246866 Hom.: 0 AF XY: 0.000263 AC XY: 35 AN XY: 133190

Gnomad AFR exome AF: 0.00373

Gnomad AMR exome AF: 0.000233

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.000101

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000268

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.000145 AC: 212 AN: 1459534 Hom.: 1 Cov.: 32 AF XY: 0.000132 AC XY: 96 AN XY: 725638

Gnomad4 AFR exome AF: 0.00422

Gnomad4 AMR exome AF: 0.000202

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000117

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000306

Gnomad4 OTH exome AF: 0.000265

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152274 Hom.: 1 Cov.: 33 AF XY: 0.00107 AC XY: 80 AN XY: 74456

Gnomad4 AFR AF: 0.00380

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000293 Hom.: 0

Bravo AF: 0.00141

ESP6500AA AF: 0.00409 AC: 18

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000354 AC: 43

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 15, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Sep 20, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 06, 2021	- -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 20, 2021

The c.6751C>T (p.R2251W) alteration is located in exon 26 (coding exon 25) of the COL6A3 gene. This alteration results from a C to T substitution at nucleotide position 6751, causing the arginine (R) at amino acid position 2251 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 15, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Pathogenic	0.20
Cadd	Pathogenic	27
Dann	Uncertain	0.98
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D;.
M_CAP	Pathogenic	0.40	D
MetaRNN	Benign	0.027	T;T;T;T;T
MetaSVM	Pathogenic	0.90	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Pathogenic	-4.7	D;D;D;.;D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;D;D;.;D
Sift4G	Pathogenic	0.0	D;D;D;D;D
Polyphen		1.0	D;D;.;.;D
Vest4		0.51
MVP		0.94
MPC		0.15
ClinPred		0.12	T
GERP RS		3.4
Varity_R		0.38
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.047
dbscSNV1_RF	Benign	0.23
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs116690555; hg19: chr2-238261167; COSMIC: COSV55088170; COSMIC: COSV55088170;