rs78224483

Variant summary

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

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

2
Splicing: ADA: 0.00001802
2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: -0.836
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]

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=-0.86).
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 GnomAd4 at 40 AD,AR gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL6A1NM_001848.3 linkuse as main transcriptc.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
COL6A1ENST00000361866.8 linkuse as main transcriptc.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
show subpopulations
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
show subpopulations
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
show subpopulations
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
show subpopulations
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:11
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6
Likely benign, no assertion criteria providedclinical testingGenetic 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 submitterclinical testingEurofins Ntd Llc (ga)Oct 14, 2014- -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Benign, criteria provided, single submitterclinical testingGeneDxFeb 17, 2016This 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. -
Benign, no assertion criteria providedclinical testingClinical Genetics, Academic Medical Center-- -
Benign, no assertion criteria providedclinical testingJoint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+-- -
not provided Benign:2
Benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Likely benign, no assertion criteria providedclinical testingLaboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)-- -
Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A Benign:1
Benign, criteria provided, single submitterclinical testingAthena DiagnosticsMay 31, 2017- -
Bethlem myopathy 1A Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 31, 2024- -
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This 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
-0.86
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

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

Other links and lift over

dbSNP: rs78224483; hg19: chr21-47421870; API