2-237378645-C-A

Variant names:

• chr2-237378645-C-A
• rs77181645
• NM_004369.4:c.2488G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004369.4(COL6A3):​c.2488G>T​(p.Ala830Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00885 in 1,612,522 control chromosomes in the GnomAD database, including 533 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A830T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.012 (66 hom., cov: 33)
  • Exomes 𝑓: 0.0085 (467 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0430
• Publications: 12 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 (MetaRNN=0.001642257).
• BP6: Variant 2-237378645-C-A is Benign according to our data. Variant chr2-237378645-C-A is described in ClinVar as Benign. ClinVar VariationId is 94916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0562 is higher than 0.05.

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.2488G>T	p.Ala830Ser	missense	Exon 6 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.1870G>T	p.Ala624Ser	missense	Exon 5 of 43	NP_476508.2
	COL6A3	NM_057165.5		c.1870G>T	p.Ala624Ser	missense	Exon 5 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.2488G>T	p.Ala830Ser	missense	Exon 6 of 44	ENSP00000295550.4
	COL6A3	ENST00000392004.7	TSL:1	c.1870G>T	p.Ala624Ser	missense	Exon 5 of 8	ENSP00000375861.3
	COL6A3	ENST00000472056.5	TSL:1	c.677-1301G>T		intron	N/A	ENSP00000418285.1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1850 AN: 152162 Hom.: 65 Cov.: 33

Gnomad AFR AF: 0.00237

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0592

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.0456

Gnomad SAS AF: 0.0333

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000941

Gnomad OTH AF: 0.0115

GnomAD2 exomes AF: 0.0265 AC: 6653 AN: 251296 AF XY: 0.0237

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.112

Gnomad ASJ exome AF: 0.000794

Gnomad EAS exome AF: 0.0432

Gnomad FIN exome AF: 0.0288

Gnomad NFE exome AF: 0.00146

Gnomad OTH exome AF: 0.0184

GnomAD4 exome AF: 0.00850 AC: 12416 AN: 1460242 Hom.: 467 Cov.: 33 AF XY: 0.00873 AC XY: 6342 AN XY: 726428

African (AFR) AF: 0.00171 AC: 57 AN: 33428

American (AMR) AF: 0.106 AC: 4722 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00122 AC: 32 AN: 26136

East Asian (EAS) AF: 0.0487 AC: 1933 AN: 39700

South Asian (SAS) AF: 0.0318 AC: 2738 AN: 86176

European-Finnish (FIN) AF: 0.0266 AC: 1423 AN: 53408

Middle Eastern (MID) AF: 0.000676 AC: 3 AN: 4438

European-Non Finnish (NFE) AF: 0.000780 AC: 867 AN: 1111998

Other (OTH) AF: 0.0106 AC: 641 AN: 60236

GnomAD4 genome AF: 0.0121 AC: 1850 AN: 152280 Hom.: 66 Cov.: 33 AF XY: 0.0152 AC XY: 1131 AN XY: 74468

African (AFR) AF: 0.00236 AC: 98 AN: 41552

American (AMR) AF: 0.0594 AC: 908 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3470

East Asian (EAS) AF: 0.0451 AC: 234 AN: 5184

South Asian (SAS) AF: 0.0331 AC: 160 AN: 4828

European-Finnish (FIN) AF: 0.0339 AC: 360 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000941 AC: 64 AN: 68012

Other (OTH) AF: 0.0114 AC: 24 AN: 2114

Alfa AF: 0.00510 Hom.: 16

Bravo AF: 0.0143

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.0226 AC: 2748

Asia WGS AF: 0.0540 AC: 188 AN: 3478

EpiCase AF: 0.000709

EpiControl AF: 0.000356

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	12
DANN	Benign	0.88
DEOGEN2	Benign	0.17	T
Eigen	Benign	-0.59
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.70	T
MetaRNN	Benign	0.0016	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.63	N
PhyloP100		0.043
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.081
Sift	Benign	0.28	T
Sift4G	Benign	0.073	T
Polyphen		0.86	P
Vest4		0.14
MPC		0.17
ClinPred		0.0030	T
GERP RS		0.19
Varity_R		0.054
gMVP		0.25
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs77181645; hg19: chr2-238287288; COSMIC: COSV55094227;