rs78224483

chr21-46001956-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001848.3(COL6A1):c.1957-5C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,611,704 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 34)
  • Exomes 𝑓: 0.020 (349 hom.)
• Consequence: COL6A1 NM_001848.3 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001802
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.836

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 (BayesDel_noAF=-0.86).
• BP6: Variant 21-46001956-C-T is Benign according to our data. Variant chr21-46001956-C-T is described in ClinVar as [Benign]. Clinvar id is 93843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46001956-C-T is described in Lovd as [Benign]. Variant chr21-46001956-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0172 (2615/152260) while in subpopulation NFE AF= 0.0264 (1796/67992). AF 95% confidence interval is 0.0254. There are 40 homozygotes in gnomad4. There are 1266 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 40 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.1957-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.1957-5C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2615 AN: 152142 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0148

GnomAD3 exomes AF: 0.0171 AC: 4123 AN: 241412 Hom.: 48 AF XY: 0.0172 AC XY: 2261 AN XY: 131366

Gnomad AFR exome AF: 0.00340

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00221

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0199 AC: 28998 AN: 1459444 Hom.: 349 Cov.: 35 AF XY: 0.0198 AC XY: 14367 AN XY: 726016

Gnomad4 AFR exome AF: 0.00281

Gnomad4 AMR exome AF: 0.00717

Gnomad4 ASJ exome AF: 0.0293

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00192

Gnomad4 FIN exome AF: 0.0290

Gnomad4 NFE exome AF: 0.0226

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0172 AC: 2615 AN: 152260 Hom.: 40 Cov.: 34 AF XY: 0.0170 AC XY: 1266 AN XY: 74444

Gnomad4 AFR AF: 0.00387

Gnomad4 AMR AF: 0.0127

Gnomad4 ASJ AF: 0.0254

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.0309

Gnomad4 NFE AF: 0.0264

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0227 Hom.: 27

Bravo AF: 0.0143

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0227

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 14, 2014	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 17, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Athena Diagnostics

May 31, 2017

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Collagen 6-related myopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Likely benign, no assertion criteria provided

clinical testing

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
Cadd	Benign	0.046
Dann	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0080
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: rs78224483; hg19: chr21-47421870;