21-46003475-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):c.2549G>A(p.Arg850His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.304 in 1,608,614 control chromosomes in the GnomAD database, including 75,844 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. R850S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.32 (8173 hom., cov: 34)
  • Exomes 𝑓: 0.30 (67671 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.118

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007473856).
• BP6: Variant 21-46003475-G-A is Benign according to our data. Variant chr21-46003475-G-A is described in ClinVar as [Benign]. Clinvar id is 93861.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46003475-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.399 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.2549G>A	p.Arg850His	missense_variant	35/35	ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.2549G>A	p.Arg850His	missense_variant	35/35	1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.321 AC: 48807 AN: 152078 Hom.: 8165 Cov.: 34

Gnomad AFR AF: 0.404

Gnomad AMI AF: 0.181

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.230

Gnomad EAS AF: 0.159

Gnomad SAS AF: 0.217

Gnomad FIN AF: 0.277

Gnomad MID AF: 0.209

Gnomad NFE AF: 0.304

Gnomad OTH AF: 0.298

GnomAD3 exomes AF: 0.283 AC: 68262 AN: 240858 Hom.: 10157 AF XY: 0.278 AC XY: 36713 AN XY: 131912

Gnomad AFR exome AF: 0.407

Gnomad AMR exome AF: 0.301

Gnomad ASJ exome AF: 0.229

Gnomad EAS exome AF: 0.147

Gnomad SAS exome AF: 0.226

Gnomad FIN exome AF: 0.274

Gnomad NFE exome AF: 0.306

Gnomad OTH exome AF: 0.275

GnomAD4 exome AF: 0.302 AC: 439372 AN: 1456418 Hom.: 67671 Cov.: 71 AF XY: 0.298 AC XY: 216249 AN XY: 724694

Gnomad4 AFR exome AF: 0.408

Gnomad4 AMR exome AF: 0.299

Gnomad4 ASJ exome AF: 0.233

Gnomad4 EAS exome AF: 0.189

Gnomad4 SAS exome AF: 0.231

Gnomad4 FIN exome AF: 0.272

Gnomad4 NFE exome AF: 0.312

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.321 AC: 48847 AN: 152196 Hom.: 8173 Cov.: 34 AF XY: 0.319 AC XY: 23765 AN XY: 74408

Gnomad4 AFR AF: 0.404

Gnomad4 AMR AF: 0.324

Gnomad4 ASJ AF: 0.230

Gnomad4 EAS AF: 0.160

Gnomad4 SAS AF: 0.218

Gnomad4 FIN AF: 0.277

Gnomad4 NFE AF: 0.304

Gnomad4 OTH AF: 0.295

Alfa AF: 0.297 Hom.: 13792

Bravo AF: 0.330

TwinsUK AF: 0.305 AC: 1131

ALSPAC AF: 0.311 AC: 1197

ESP6500AA AF: 0.398 AC: 1739

ESP6500EA AF: 0.309 AC: 2627

ExAC AF: 0.283 AC: 34130

Asia WGS AF: 0.178 AC: 622 AN: 3478

EpiCase AF: 0.305

EpiControl AF: 0.301

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:7

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 15, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 17, 2012	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 22, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Bethlem myopathy 1A Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 30, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Ullrich congenital muscular dystrophy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 30, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	13
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.12	N
LIST_S2	Benign	0.54	T;T
MetaRNN	Benign	0.0075	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N;.
REVEL	Benign	0.13
Sift	Benign	0.16	T;.
Sift4G	Benign	0.12	T;T
Polyphen		0.0020	B;.
Vest4		0.055
MPC		0.28
ClinPred		0.0042	T
GERP RS		0.71
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.025
gMVP		0.32

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

Publications

LitVar

Other links and lift over

dbSNP: rs1053312; hg19: chr21-47423389; COSMIC: COSV62611655; COSMIC: COSV62611655;