rs182804464

Positions:

Variant summary

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

The NM_001848.3(COL6A1):c.1814-6C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0123 in 1,613,892 control chromosomes in the GnomAD database, including 182 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0089 ( 14 hom., cov: 35)

Exomes 𝑓: 0.013 ( 168 hom. )

Consequence

COL6A1
NM_001848.3 splice_region, intron

Scores

Splicing: ADA: 0.03446

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.475

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:

COL6A1 (HGNC:):

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=-0.54).

BP6

Variant 21-46000753-C-G is Benign according to our data. Variant chr21-46000753-C-G is described in ClinVar as [Benign]. Clinvar id is 93830.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46000753-C-G is described in Lovd as [Benign]. Variant chr21-46000753-C-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0089 (1356/152340) while in subpopulation NFE AF= 0.0137 (935/68022). AF 95% confidence interval is 0.013. There are 14 homozygotes in gnomad4. There are 664 alleles in male gnomad4 subpopulation. Median coverage is 35. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.1814-6C>G		splice_region_variant, intron_variant		ENST00000361866.8	NP_001839.2	P12109A0A384P5H7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8 linkuse as main transcript	c.1814-6C>G		splice_region_variant, intron_variant		1	NM_001848.3	ENSP00000355180.3		P12109
COL6A1	ENST00000466285.1 linkuse as main transcript	n.331-6C>G		splice_region_variant, intron_variant		3

Frequencies

GnomAD3 genomes

AF:

0.00893

AC:

1359

AN:

152222

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00256

Gnomad AMI

AF:

0.0230

Gnomad AMR

AF:

0.00340

Gnomad ASJ

AF:

0.00374

Gnomad EAS

AF:

0.000578

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.0187

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0138

Gnomad OTH

AF:

0.00861

GnomAD3 exomes

AF:

0.0101

AC:

2545

AN:

251424

Hom.:

AF XY:

0.0101

AC XY:

1373

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00278

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00274

Gnomad FIN exome

AF:

0.0194

Gnomad NFE exome

AF:

0.0161

Gnomad OTH exome

AF:

0.0106

GnomAD4 exome

AF:

0.0126

AC:

18448

AN:

1461552

Hom.:

168

Cov.:

AF XY:

0.0123

AC XY:

8963

AN XY:

727118

show subpopulations

Gnomad4 AFR exome

AF:

0.00206

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00283

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00371

Gnomad4 FIN exome

AF:

0.0201

Gnomad4 NFE exome

AF:

0.0146

Gnomad4 OTH exome

AF:

0.00976

GnomAD4 genome

AF:

0.00890

AC:

1356

AN:

152340

Hom.:

Cov.:

AF XY:

0.00891

AC XY:

664

AN XY:

74494

show subpopulations

Gnomad4 AFR

AF:

0.00255

Gnomad4 AMR

AF:

0.00333

Gnomad4 ASJ

AF:

0.00374

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.00207

Gnomad4 FIN

AF:

0.0187

Gnomad4 NFE

AF:

0.0137

Gnomad4 OTH

AF:

0.00852

Alfa

AF:

0.00517

Hom.:

Bravo

AF:

0.00756

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0109

EpiControl

AF:

0.0115

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 04, 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. -
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	Eurofins Ntd Llc (ga)	Aug 24, 2012	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 30, 2018	- -

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 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.54

CADD

Benign

DANN

Benign

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.034

dbscSNV1_RF

Benign

0.15

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.21

Position offset: -39

DS_AL_spliceai

0.20

Position offset: 6

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