rs200727020

Positions:

chr21-46002208-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.2067-10T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.2067-10T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001848.3	ENSP00000355180	P1

Frequencies

GnomAD3 genomes

AF:

0.00287

AC:

436

AN:

152156

Hom.:

Cov.:

show subpopulations

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.:

AF XY:

0.00229

AC XY:

268

AN XY:

116838

show subpopulations

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.:

Cov.:

AF XY:

0.00418

AC XY:

3004

AN XY:

718014

show subpopulations

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.:

Cov.:

AF XY:

0.00248

AC XY:

185

AN XY:

74448

show subpopulations

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.:

Bravo

AF:

0.00286

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 05, 2021	- -
Likely 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	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

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

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

Labcorp Genetics (formerly Invitae), Labcorp

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over