rs11553518

Variant names:

• chr21-46003126-A-G
• rs11553518
• NM_001848.3:c.2441A>G

Variant summary

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

The NM_001848.3(COL6A1):​c.2441A>G​(p.Lys814Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0165 in 1,614,024 control chromosomes in the GnomAD database, including 1,375 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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. K814Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.015 (115 hom., cov: 34)
  • Exomes 𝑓: 0.017 (1260 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 4.75
• Publications: 13 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=0.0024976134).
• BP6: Variant 21-46003126-A-G is Benign according to our data. Variant chr21-46003126-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.143 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. 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
	COL6A1	NM_001848.3	MANE Select	c.2441A>G	p.Lys814Arg	missense	Exon 34 of 35	NP_001839.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.2441A>G	p.Lys814Arg	missense	Exon 34 of 35	ENSP00000355180.3
	COL6A1	ENST00000498614.5	TSL:1	n.675A>G		non_coding_transcript_exon	Exon 5 of 6
	COL6A1	ENST00000866134.1		c.755A>G	p.Lys252Arg	missense	Exon 6 of 7	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.0150 AC: 2277 AN: 152162 Hom.: 115 Cov.: 34

Gnomad AFR AF: 0.00606

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0154

Gnomad ASJ AF: 0.0156

Gnomad EAS AF: 0.152

Gnomad SAS AF: 0.0977

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00604

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0287 AC: 7212 AN: 251294 AF XY: 0.0314

Gnomad AFR exome AF: 0.00542

Gnomad AMR exome AF: 0.0133

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.140

Gnomad FIN exome AF: 0.00333

Gnomad NFE exome AF: 0.00646

Gnomad OTH exome AF: 0.0205

GnomAD4 exome AF: 0.0167 AC: 24418 AN: 1461744 Hom.: 1260 Cov.: 33 AF XY: 0.0191 AC XY: 13864 AN XY: 727180

African (AFR) AF: 0.00583 AC: 195 AN: 33476

American (AMR) AF: 0.0140 AC: 626 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 443 AN: 26130

East Asian (EAS) AF: 0.179 AC: 7104 AN: 39692

South Asian (SAS) AF: 0.0978 AC: 8437 AN: 86256

European-Finnish (FIN) AF: 0.00347 AC: 185 AN: 53376

Middle Eastern (MID) AF: 0.0272 AC: 157 AN: 5766

European-Non Finnish (NFE) AF: 0.00545 AC: 6065 AN: 1111942

Other (OTH) AF: 0.0200 AC: 1206 AN: 60384

GnomAD4 genome AF: 0.0150 AC: 2277 AN: 152280 Hom.: 115 Cov.: 34 AF XY: 0.0174 AC XY: 1294 AN XY: 74444

African (AFR) AF: 0.00606 AC: 252 AN: 41566

American (AMR) AF: 0.0154 AC: 236 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 54 AN: 3466

East Asian (EAS) AF: 0.152 AC: 784 AN: 5164

South Asian (SAS) AF: 0.0982 AC: 474 AN: 4826

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00603 AC: 410 AN: 68010

Other (OTH) AF: 0.0152 AC: 32 AN: 2112

Alfa AF: 0.0131 Hom.: 142

Bravo AF: 0.0143

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00441 AC: 17

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.00709 AC: 61

ExAC AF: 0.0304 AC: 3691

Asia WGS AF: 0.0950 AC: 329 AN: 3478

EpiCase AF: 0.00802

EpiControl AF: 0.00794

ClinVar

ClinVar submissions as Germline

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	0.096
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.28
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T
MetaRNN	Benign	0.0025	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	1.8	L
PhyloP100		4.7
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.9	N
REVEL	Benign	0.27
Sift	Benign	0.067	T
Sift4G	Uncertain	0.044	D
Polyphen		0.016	B
Vest4		0.30
MPC		0.21
ClinPred		0.015	T
GERP RS		3.4
Varity_R		0.089
gMVP		0.21
Mutation Taster		=92/8	polymorphism (auto)

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: rs11553518; hg19: chr21-47423040; COSMIC: COSV62612188; COSMIC: COSV62612188;