2-237336365-G-A

Variant names:

• chr2-237336365-G-A
• rs112928650
• NM_004369.4:c.8735C>T

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.8735C>T​(p.Pro2912Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00277 in 1,614,148 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P2912P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0044 (17 hom., cov: 33)
  • Exomes 𝑓: 0.0026 (61 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.63
• Publications: 4 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=0.002975285).
• BP6: Variant 2-237336365-G-A is Benign according to our data. Variant chr2-237336365-G-A is described in ClinVar as Benign. ClinVar VariationId is 166936.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0044 (670/152324) while in subpopulation EAS AF = 0.0328 (170/5188). AF 95% confidence interval is 0.0287. There are 17 homozygotes in GnomAd4. There are 465 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 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.8735C>T	p.Pro2912Leu	missense	Exon 40 of 44	NP_004360.2
	COL6A3	NM_057167.4		c.8117C>T	p.Pro2706Leu	missense	Exon 39 of 43	NP_476508.2
	COL6A3	NM_057166.5		c.6914C>T	p.Pro2305Leu	missense	Exon 37 of 41	NP_476507.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.8735C>T	p.Pro2912Leu	missense	Exon 40 of 44	ENSP00000295550.4
	COL6A3	ENST00000472056.5	TSL:1	c.6914C>T	p.Pro2305Leu	missense	Exon 37 of 41	ENSP00000418285.1
	COL6A3	ENST00000353578.9	TSL:5	c.8117C>T	p.Pro2706Leu	missense	Exon 39 of 43	ENSP00000315873.4

Frequencies

GnomAD3 genomes AF: 0.00440 AC: 669 AN: 152206 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.000314

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0325

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0396

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00613 AC: 1542 AN: 251362 AF XY: 0.00603

Gnomad AFR exome AF: 0.000432

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0319

Gnomad FIN exome AF: 0.0333

Gnomad NFE exome AF: 0.00136

Gnomad OTH exome AF: 0.00489

GnomAD4 exome AF: 0.00260 AC: 3801 AN: 1461824 Hom.: 61 Cov.: 34 AF XY: 0.00255 AC XY: 1858 AN XY: 727208

African (AFR) AF: 0.000179 AC: 6 AN: 33478

American (AMR) AF: 0.000335 AC: 15 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0317 AC: 1259 AN: 39700

South Asian (SAS) AF: 0.000846 AC: 73 AN: 86252

European-Finnish (FIN) AF: 0.0319 AC: 1702 AN: 53410

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5766

European-Non Finnish (NFE) AF: 0.000498 AC: 554 AN: 1111972

Other (OTH) AF: 0.00313 AC: 189 AN: 60388

GnomAD4 genome AF: 0.00440 AC: 670 AN: 152324 Hom.: 17 Cov.: 33 AF XY: 0.00624 AC XY: 465 AN XY: 74490

African (AFR) AF: 0.000313 AC: 13 AN: 41574

American (AMR) AF: 0.000457 AC: 7 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0328 AC: 170 AN: 5188

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.0396 AC: 420 AN: 10612

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

European-Non Finnish (NFE) AF: 0.000750 AC: 51 AN: 68030

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00200 Hom.: 8

Bravo AF: 0.00193

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.00589 AC: 714

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Benign	0.37
DEOGEN2	Benign	0.23	T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.23	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		1.6
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.19
Sift	Benign	0.039	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.19
MVP		0.86
MPC		0.15
ClinPred		0.023	T
GERP RS		0.76
Varity_R		0.048
gMVP		0.086
Mutation Taster		=97/3	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: rs112928650; hg19: chr2-238245008; COSMIC: COSV55102081; COSMIC: COSV55102081;