rs78398512

Variant names:

• chr2-237358991-T-C
• rs78398512
• NM_004369.4:c.6408+44A>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.6408+44A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00189 in 1,584,230 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (19 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (20 hom.)
• Consequence: COL6A3 NM_004369.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.372
• Publications: 2 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, AR, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

  Inheritance: AD, AR 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: Illumina, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics, Orphanet
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp
• 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 (BayesDel_noAF=-0.89).
• BP6: Variant 2-237358991-T-C is Benign according to our data. Variant chr2-237358991-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00839 (1278/152294) while in subpopulation AFR AF = 0.0273 (1136/41550). AF 95% confidence interval is 0.026. There are 19 homozygotes in GnomAd4. There are 615 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 19 AD,AR,SD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.6408+44A>G		intron_variant	Intron 20 of 43	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.5790+44A>G		intron_variant	Intron 19 of 42		NP_476508.2
COL6A3	NM_057166.5	c.4587+44A>G		intron_variant	Intron 17 of 40		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.6408+44A>G		intron_variant	Intron 20 of 43	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.4587+44A>G		intron_variant	Intron 17 of 40	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.5790+44A>G		intron_variant	Intron 19 of 42	5		ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.00830 AC: 1263 AN: 152176 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.00716

GnomAD2 exomes AF: 0.00263 AC: 661 AN: 251312 AF XY: 0.00203

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00367

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00119 AC: 1709 AN: 1431936 Hom.: 20 Cov.: 28 AF XY: 0.00110 AC XY: 785 AN XY: 714304

African (AFR) AF: 0.0257 AC: 840 AN: 32648

American (AMR) AF: 0.00385 AC: 172 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.0000386 AC: 1 AN: 25928

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.0000935 AC: 8 AN: 85578

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53400

Middle Eastern (MID) AF: 0.00630 AC: 36 AN: 5712

European-Non Finnish (NFE) AF: 0.000424 AC: 460 AN: 1085054

Other (OTH) AF: 0.00322 AC: 191 AN: 59388

GnomAD4 genome AF: 0.00839 AC: 1278 AN: 152294 Hom.: 19 Cov.: 33 AF XY: 0.00826 AC XY: 615 AN XY: 74476

African (AFR) AF: 0.0273 AC: 1136 AN: 41550

American (AMR) AF: 0.00588 AC: 90 AN: 15302

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

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

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000500 AC: 34 AN: 68022

Other (OTH) AF: 0.00709 AC: 15 AN: 2116

Alfa AF: 0.00884 Hom.: 11

Bravo AF: 0.00969

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 05, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 10, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.43
DANN	Benign	0.46
PhyloP100		0.37
Mutation Taster		=100/0	polymorphism

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: rs78398512; hg19: chr2-238267634;