rs200727020

chr21-46002208-T-C

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.2067-10T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00425 in 1,597,336 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 34)
  • Exomes 𝑓: 0.0044 (15 hom.)
• Consequence: COL6A1 NM_001848.3 splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001928
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.54

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=-0.83).
• BP6: Variant 21-46002208-T-C is Benign according to our data. Variant chr21-46002208-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 93846.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46002208-T-C is described in Lovd as [Benign]. Variant chr21-46002208-T-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00286 (436/152274) while in subpopulation NFE AF= 0.00503 (342/67988). AF 95% confidence interval is 0.00459. There are 2 homozygotes in gnomad4. There are 185 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A1	NM_001848.3	c.2067-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361866.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A1	ENST00000361866.8	c.2067-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001848.3	P1

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 436 AN: 152156 Hom.: 2 Cov.: 34

Gnomad AFR AF: 0.000941

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00169

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00503

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00244 AC: 517 AN: 212176 Hom.: 2 AF XY: 0.00229 AC XY: 268 AN XY: 116838

Gnomad AFR exome AF: 0.00102

Gnomad AMR exome AF: 0.00226

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000321

Gnomad FIN exome AF: 0.00190

Gnomad NFE exome AF: 0.00405

Gnomad OTH exome AF: 0.00321

GnomAD4 exome AF: 0.00439 AC: 6348 AN: 1445062 Hom.: 15 Cov.: 35 AF XY: 0.00418 AC XY: 3004 AN XY: 718014

Gnomad4 AFR exome AF: 0.000660

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.000194

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000202

Gnomad4 FIN exome AF: 0.00230

Gnomad4 NFE exome AF: 0.00529

Gnomad4 OTH exome AF: 0.00380

GnomAD4 genome AF: 0.00286 AC: 436 AN: 152274 Hom.: 2 Cov.: 34 AF XY: 0.00248 AC XY: 185 AN XY: 74448

Gnomad4 AFR AF: 0.000938

Gnomad4 AMR AF: 0.00196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00169

Gnomad4 NFE AF: 0.00503

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00301 Hom.: 1

Bravo AF: 0.00286

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 07, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 26, 2017	- -

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. -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	3.8
Dann	Benign	0.30

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00019
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.020		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: rs200727020; hg19: chr21-47422122;