rs114750216

Variant names:

• chr2-237387712-G-A
• rs114750216
• NM_004369.4:c.1182C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237387712-G-A
• chr2-237387712-G-T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004369.4(COL6A3):​c.1182C>T​(p.Thr394Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00585 in 1,613,934 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 0.0044 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0060 (34 hom.)
• Consequence: COL6A3 NM_004369.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.230
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 2-237387712-G-A is Benign according to our data. Variant chr2-237387712-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94902.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.23 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0044 (670/152296) while in subpopulation NFE AF = 0.00598 (407/68032). AF 95% confidence interval is 0.0055. There are 5 homozygotes in GnomAd4. There are 309 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AD,AR,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.1182C>T	p.Thr394Thr	synonymous	Exon 4 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.564C>T	p.Thr188Thr	synonymous	Exon 3 of 43	NP_476508.2
	COL6A3	NM_057165.5		c.564C>T	p.Thr188Thr	synonymous	Exon 3 of 8	NP_476506.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.1182C>T	p.Thr394Thr	synonymous	Exon 4 of 44	ENSP00000295550.4
	COL6A3	ENST00000392004.7	TSL:1	c.564C>T	p.Thr188Thr	synonymous	Exon 3 of 8	ENSP00000375861.3
	COL6A3	ENST00000433762.1	TSL:1	c.1182C>T	p.Thr394Thr	synonymous	Exon 4 of 6	ENSP00000389539.1

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 670 AN: 152178 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00458

Gnomad ASJ AF: 0.0259

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00598

Gnomad OTH AF: 0.00527

GnomAD2 exomes AF: 0.00588 AC: 1474 AN: 250708 AF XY: 0.00612

Gnomad AFR exome AF: 0.000433

Gnomad AMR exome AF: 0.00319

Gnomad ASJ exome AF: 0.0231

Gnomad EAS exome AF: 0.000436

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00652

Gnomad OTH exome AF: 0.0113

GnomAD4 exome AF: 0.00600 AC: 8772 AN: 1461638 Hom.: 34 Cov.: 32 AF XY: 0.00607 AC XY: 4416 AN XY: 727088

African (AFR) AF: 0.000986 AC: 33 AN: 33470

American (AMR) AF: 0.00333 AC: 149 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0241 AC: 631 AN: 26134

East Asian (EAS) AF: 0.000227 AC: 9 AN: 39682

South Asian (SAS) AF: 0.00831 AC: 716 AN: 86198

European-Finnish (FIN) AF: 0.00279 AC: 149 AN: 53402

Middle Eastern (MID) AF: 0.0170 AC: 98 AN: 5768

European-Non Finnish (NFE) AF: 0.00591 AC: 6575 AN: 1111898

Other (OTH) AF: 0.00682 AC: 412 AN: 60390

GnomAD4 genome AF: 0.00440 AC: 670 AN: 152296 Hom.: 5 Cov.: 33 AF XY: 0.00415 AC XY: 309 AN XY: 74468

African (AFR) AF: 0.000987 AC: 41 AN: 41560

American (AMR) AF: 0.00458 AC: 70 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0259 AC: 90 AN: 3470

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5178

South Asian (SAS) AF: 0.00518 AC: 25 AN: 4826

European-Finnish (FIN) AF: 0.00169 AC: 18 AN: 10624

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.00598 AC: 407 AN: 68032

Other (OTH) AF: 0.00522 AC: 11 AN: 2108

Alfa AF: 0.00765 Hom.: 3

Bravo AF: 0.00488

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00706

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A3-related disorder (1)
-	-	1	Collagen 6-related myopathy (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
BayesDel_noAF	Benign	-0.41
CADD	Benign	11
DANN	Benign	0.77
PhyloP100		0.23
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: rs114750216; hg19: chr2-238296355; COSMIC: COSV55099695;