rs73998889

Positions:

• chr2-237360038-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.6282+50C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0072 in 1,585,368 control chromosomes in the GnomAD database, including 363 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.028 (174 hom., cov: 32)
  • Exomes 𝑓: 0.0050 (189 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.84

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 2-237360038-G-A is Benign according to our data. Variant chr2-237360038-G-A is described in ClinVar as [Benign]. Clinvar id is 94960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-237360038-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0849 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6282+50C>T		intron_variant		ENST00000295550.9	NP_004360.2
COL6A3	NM_057166.5	c.4461+50C>T		intron_variant			NP_476507.3
COL6A3	NM_057167.4	c.5664+50C>T		intron_variant			NP_476508.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6282+50C>T		intron_variant		1	NM_004369.4	ENSP00000295550	P1
COL6A3	ENST00000472056.5	c.4461+50C>T		intron_variant		1		ENSP00000418285
COL6A3	ENST00000353578.9	c.5664+50C>T		intron_variant		5		ENSP00000315873

Frequencies

GnomAD3 genomes AF: 0.0278 AC: 4227 AN: 151968 Hom.: 173 Cov.: 32

Gnomad AFR AF: 0.0874

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.00547

Gnomad EAS AF: 0.00369

Gnomad SAS AF: 0.00914

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0380

Gnomad NFE AF: 0.00268

Gnomad OTH AF: 0.0272

GnomAD3 exomes AF: 0.0103 AC: 2550 AN: 246956 Hom.: 76 AF XY: 0.00873 AC XY: 1165 AN XY: 133520

Gnomad AFR exome AF: 0.0887

Gnomad AMR exome AF: 0.0110

Gnomad ASJ exome AF: 0.00583

Gnomad EAS exome AF: 0.00313

Gnomad SAS exome AF: 0.00948

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00274

Gnomad OTH exome AF: 0.00944

GnomAD4 exome AF: 0.00501 AC: 7183 AN: 1433282 Hom.: 189 Cov.: 28 AF XY: 0.00489 AC XY: 3491 AN XY: 714390

Gnomad4 AFR exome AF: 0.0882

Gnomad4 AMR exome AF: 0.0119

Gnomad4 ASJ exome AF: 0.00632

Gnomad4 EAS exome AF: 0.00137

Gnomad4 SAS exome AF: 0.00923

Gnomad4 FIN exome AF: 0.0000937

Gnomad4 NFE exome AF: 0.00178

Gnomad4 OTH exome AF: 0.0116

GnomAD4 genome AF: 0.0278 AC: 4228 AN: 152086 Hom.: 174 Cov.: 32 AF XY: 0.0275 AC XY: 2043 AN XY: 74344

Gnomad4 AFR AF: 0.0873

Gnomad4 AMR AF: 0.0182

Gnomad4 ASJ AF: 0.00547

Gnomad4 EAS AF: 0.00350

Gnomad4 SAS AF: 0.00915

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00268

Gnomad4 OTH AF: 0.0270

Alfa AF: 0.0164 Hom.: 19

Bravo AF: 0.0322

Asia WGS AF: 0.0160 AC: 55 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 05, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 07, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.91
DANN	Benign	0.59

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

Publications

LitVar

Other links and lift over

dbSNP: rs73998889; hg19: chr2-238268681;