rs111595697

Variant names:

• chr2-237340988-G-A
• rs111595697
• NM_004369.4:c.7928C>T

Your query was ambiguous. Multiple possible variants found:

• chr2-237340988-G-A
• chr2-237340988-G-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.7928C>T​(p.Ala2643Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,614,164 control chromosomes in the GnomAD database, including 20 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A2643S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0045 (8 hom., cov: 31)
  • Exomes 𝑓: 0.0014 (12 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 1.82
• Publications: 6 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: AR, AD, SD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Ambry Genetics
• collagen 6-related myopathy

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

  Inheritance: AR, AD, SD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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=0.00923264).
• BP6: Variant 2-237340988-G-A is Benign according to our data. Variant chr2-237340988-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 128821.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 = 0.0045 (685/152288) while in subpopulation AFR AF = 0.0136 (565/41560). AF 95% confidence interval is 0.0127. There are 8 homozygotes in GnomAd4. There are 321 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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.7928C>T	p.Ala2643Val	missense	Exon 38 of 44	NP_004360.2	D9ZGF2
	COL6A3	NM_057167.4		c.7310C>T	p.Ala2437Val	missense	Exon 37 of 43	NP_476508.2	P12111-2
	COL6A3	NM_057166.5		c.6107C>T	p.Ala2036Val	missense	Exon 35 of 41	NP_476507.3	P12111-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A3	ENST00000295550.9	TSL:1 MANE Select	c.7928C>T	p.Ala2643Val	missense	Exon 38 of 44	ENSP00000295550.4	P12111-1
	COL6A3	ENST00000472056.5	TSL:1	c.6107C>T	p.Ala2036Val	missense	Exon 35 of 41	ENSP00000418285.1	P12111-4
	COL6A3	ENST00000353578.9	TSL:5	c.7310C>T	p.Ala2437Val	missense	Exon 37 of 43	ENSP00000315873.4	P12111-2

Frequencies

GnomAD3 genomes AF: 0.00444 AC: 676 AN: 152170 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.0134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00113

Gnomad OTH AF: 0.00621

GnomAD2 exomes AF: 0.00192 AC: 483 AN: 250964 AF XY: 0.00155

Gnomad AFR exome AF: 0.0130

Gnomad AMR exome AF: 0.00147

Gnomad ASJ exome AF: 0.000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000785

Gnomad NFE exome AF: 0.00148

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00135 AC: 1977 AN: 1461876 Hom.: 12 Cov.: 35 AF XY: 0.00125 AC XY: 909 AN XY: 727242

African (AFR) AF: 0.0132 AC: 441 AN: 33480

American (AMR) AF: 0.00148 AC: 66 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00103 AC: 27 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000487 AC: 42 AN: 86258

European-Finnish (FIN) AF: 0.000693 AC: 37 AN: 53420

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.00108 AC: 1197 AN: 1112000

Other (OTH) AF: 0.00225 AC: 136 AN: 60396

GnomAD4 genome AF: 0.00450 AC: 685 AN: 152288 Hom.: 8 Cov.: 31 AF XY: 0.00431 AC XY: 321 AN XY: 74450

African (AFR) AF: 0.0136 AC: 565 AN: 41560

American (AMR) AF: 0.00150 AC: 23 AN: 15296

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4818

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00113 AC: 77 AN: 68024

Other (OTH) AF: 0.00614 AC: 13 AN: 2116

Alfa AF: 0.00209 Hom.: 1

Bravo AF: 0.00475

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.0113 AC: 50

ESP6500EA AF: 0.000814 AC: 7

ExAC AF: 0.00222 AC: 269

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.00136

EpiControl AF: 0.00190

ClinVar

ClinVar submissions

Significance: Benign/Likely 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	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.26
CADD	Benign	16
DANN	Benign	0.80
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.79
FATHMM_MKL	Benign	0.20	N
LIST_S2	Uncertain	0.87	D
MetaRNN	Benign	0.0092	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.2	L
PhyloP100		1.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.31
Sift	Benign	0.041	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.52	P
Vest4		0.22
MVP		0.81
MPC		0.15
ClinPred		0.014	T
GERP RS		-3.2
Varity_R		0.075
gMVP		0.39
Mutation Taster		=99/1	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: rs111595697; hg19: chr2-238249631;