rs13051496

Variant names:

• chr21-46003595-C-T
• rs13051496
• NM_001848.3:c.2669C>T

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.2669C>T​(p.Ser890Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.198 in 1,612,760 control chromosomes in the GnomAD database, including 34,145 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 Benign (★★). Synonymous variant affecting the same amino acid position (i.e. S890S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.15 (2235 hom., cov: 36)
  • Exomes 𝑓: 0.20 (31910 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 3.21
• Publications: 31 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=0.0022459328).
• BP6: Variant 21-46003595-C-T is Benign according to our data. Variant chr21-46003595-C-T is described in ClinVar as Benign. ClinVar VariationId is 93865.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.2669C>T	p.Ser890Leu	missense	Exon 35 of 35	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.2669C>T	p.Ser890Leu	missense	Exon 35 of 35	ENSP00000355180.3
	COL6A1	ENST00000498614.5	TSL:1	n.903C>T		non_coding_transcript_exon	Exon 6 of 6
	COL6A1	ENST00000612273.2	TSL:5	c.794C>T	p.Ser265Leu	missense	Exon 6 of 7	ENSP00000483630.2

Frequencies

GnomAD3 genomes AF: 0.154 AC: 23404 AN: 152172 Hom.: 2235 Cov.: 36

Gnomad AFR AF: 0.0581

Gnomad AMI AF: 0.202

Gnomad AMR AF: 0.124

Gnomad ASJ AF: 0.160

Gnomad EAS AF: 0.0720

Gnomad SAS AF: 0.102

Gnomad FIN AF: 0.214

Gnomad MID AF: 0.120

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.142

GnomAD2 exomes AF: 0.161 AC: 39804 AN: 246710 AF XY: 0.166

Gnomad AFR exome AF: 0.0547

Gnomad AMR exome AF: 0.0858

Gnomad ASJ exome AF: 0.171

Gnomad EAS exome AF: 0.0699

Gnomad FIN exome AF: 0.219

Gnomad NFE exome AF: 0.216

Gnomad OTH exome AF: 0.179

GnomAD4 exome AF: 0.202 AC: 295295 AN: 1460470 Hom.: 31910 Cov.: 80 AF XY: 0.200 AC XY: 145438 AN XY: 726590

African (AFR) AF: 0.0564 AC: 1887 AN: 33472

American (AMR) AF: 0.0901 AC: 4028 AN: 44708

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 4378 AN: 26112

East Asian (EAS) AF: 0.0646 AC: 2563 AN: 39692

South Asian (SAS) AF: 0.112 AC: 9640 AN: 86246

European-Finnish (FIN) AF: 0.218 AC: 11406 AN: 52288

Middle Eastern (MID) AF: 0.141 AC: 815 AN: 5768

European-Non Finnish (NFE) AF: 0.224 AC: 249304 AN: 1111818

Other (OTH) AF: 0.187 AC: 11274 AN: 60366

GnomAD4 genome AF: 0.154 AC: 23403 AN: 152290 Hom.: 2235 Cov.: 36 AF XY: 0.152 AC XY: 11288 AN XY: 74460

African (AFR) AF: 0.0581 AC: 2415 AN: 41584

American (AMR) AF: 0.124 AC: 1901 AN: 15312

Ashkenazi Jewish (ASJ) AF: 0.160 AC: 555 AN: 3470

East Asian (EAS) AF: 0.0718 AC: 371 AN: 5168

South Asian (SAS) AF: 0.102 AC: 492 AN: 4828

European-Finnish (FIN) AF: 0.214 AC: 2275 AN: 10618

Middle Eastern (MID) AF: 0.112 AC: 33 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14879 AN: 67990

Other (OTH) AF: 0.141 AC: 298 AN: 2114

Alfa AF: 0.187 Hom.: 2018

Bravo AF: 0.143

TwinsUK AF: 0.225 AC: 835

ALSPAC AF: 0.216 AC: 834

ESP6500AA AF: 0.0558 AC: 246

ESP6500EA AF: 0.216 AC: 1859

ExAC AF: 0.161 AC: 19511

Asia WGS AF: 0.0740 AC: 259 AN: 3478

EpiCase AF: 0.214

EpiControl AF: 0.213

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.54
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.78	T
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		3.2
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.19
Sift	Uncertain	0.019	D
Sift4G	Benign	0.063	T
Polyphen		0.13	B
Vest4		0.10
MPC		0.34
ClinPred		0.017	T
GERP RS		4.0
Varity_R		0.18
gMVP		0.43
Mutation Taster		=100/0	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: rs13051496; hg19: chr21-47423509; COSMIC: COSV62611834; COSMIC: COSV62611834;