chr21-46001245-G-A

Position:

chr21-46001245-G-A

Variant summary

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

The NM_001848.3(COL6A1):c.1823-8G>A 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 0.00666 in 1,603,962 control chromosomes in the GnomAD database, including 179 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 0.0055 ( 15 hom., cov: 34)

Exomes 𝑓: 0.0068 ( 164 hom. )

Consequence

COL6A1
NM_001848.3 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.00002660

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.103

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:

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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 21-46001245-G-A is Benign according to our data. Variant chr21-46001245-G-A is described in ClinVar as [Benign]. Clinvar id is 93837.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46001245-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00549 (837/152324) while in subpopulation SAS AF= 0.0488 (236/4834). AF 95% confidence interval is 0.0437. There are 15 homozygotes in gnomad4. There are 522 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3 linkuse as main transcript	c.1823-8G>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	Effect	#exon/exons	TSL	MANE	Protein	Appris
COL6A1	ENST00000361866.8 linkuse as main transcript	c.1823-8G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001848.3	ENSP00000355180	P1
COL6A1	ENST00000498614.5 linkuse as main transcript	n.49G>A	non_coding_transcript_exon_variant	1/6	1
COL6A1	ENST00000463060.6 linkuse as main transcript	n.222-8G>A	splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.00550

AC:

837

AN:

152206

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00110

Gnomad AMR

AF:

0.00229

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0488

Gnomad FIN

AF:

0.0171

Gnomad MID

AF:

0.0158

Gnomad NFE

AF:

0.00494

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.00980

AC:

2382

AN:

242994

Hom.:

AF XY:

0.0126

AC XY:

1671

AN XY:

132348

show subpopulations

Gnomad AFR exome

AF:

0.000311

Gnomad AMR exome

AF:

0.00139

Gnomad ASJ exome

AF:

0.00309

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.0509

Gnomad FIN exome

AF:

0.0170

Gnomad NFE exome

AF:

0.00374

Gnomad OTH exome

AF:

0.00858

GnomAD4 exome

AF:

0.00678

AC:

9839

AN:

1451638

Hom.:

164

Cov.:

AF XY:

0.00829

AC XY:

5991

AN XY:

722310

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.00112

Gnomad4 ASJ exome

AF:

0.00364

Gnomad4 EAS exome

AF:

0.0000505

Gnomad4 SAS exome

AF:

0.0491

Gnomad4 FIN exome

AF:

0.0177

Gnomad4 NFE exome

AF:

0.00365

Gnomad4 OTH exome

AF:

0.00814

GnomAD4 genome

AF:

0.00549

AC:

837

AN:

152324

Hom.:

Cov.:

AF XY:

0.00701

AC XY:

522

AN XY:

74484

show subpopulations

Gnomad4 AFR

AF:

0.000625

Gnomad4 AMR

AF:

0.00222

Gnomad4 ASJ

AF:

0.00317

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0488

Gnomad4 FIN

AF:

0.0171

Gnomad4 NFE

AF:

0.00494

Gnomad4 OTH

AF:

0.00236

Alfa

AF:

0.00507

Hom.:

Bravo

AF:

0.00258

Asia WGS

AF:

0.0180

AC:

AN:

3478

EpiCase

AF:

0.00442

EpiControl

AF:

0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 12, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 27, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 11, 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. -

not provided

Benign:2

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+	-	- -

COL6A1-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

May 06, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Bethlem myopathy 1A

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.24

DANN

Benign

0.61

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.034

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

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