rs138976133

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001848.3(COL6A1):​c.2220G>A​(p.Pro740Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.001 in 1,594,070 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0018 ( 2 hom., cov: 34)
Exomes 𝑓: 0.00092 ( 5 hom. )

Consequence

COL6A1
NM_001848.3 synonymous

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -4.96
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 -21 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 21-46002371-G-A is Benign according to our data. Variant chr21-46002371-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 196776.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
BP7
Synonymous conserved (PhyloP=-4.96 with no splicing effect.
BS1
Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.000922 (1329/1441730) while in subpopulation MID AF= 0.00644 (37/5748). AF 95% confidence interval is 0.0048. There are 5 homozygotes in gnomad4_exome. There are 677 alleles in male gnomad4_exome subpopulation. Median coverage is 35. 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
COL6A1NM_001848.3 linkuse as main transcriptc.2220G>A p.Pro740Pro synonymous_variant 32/35 ENST00000361866.8 NP_001839.2 P12109A0A384P5H7

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL6A1ENST00000361866.8 linkuse as main transcriptc.2220G>A p.Pro740Pro synonymous_variant 32/351 NM_001848.3 ENSP00000355180.3 P12109

Frequencies

GnomAD3 genomes
AF:
0.00178
AC:
271
AN:
152222
Hom.:
2
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00328
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00164
Gnomad ASJ
AF:
0.0101
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.000207
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.000926
Gnomad OTH
AF:
0.000956
GnomAD3 exomes
AF:
0.00159
AC:
334
AN:
210698
Hom.:
3
AF XY:
0.00158
AC XY:
181
AN XY:
114610
show subpopulations
Gnomad AFR exome
AF:
0.00270
Gnomad AMR exome
AF:
0.00228
Gnomad ASJ exome
AF:
0.00880
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.000752
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00122
Gnomad OTH exome
AF:
0.00297
GnomAD4 exome
AF:
0.000922
AC:
1329
AN:
1441730
Hom.:
5
Cov.:
35
AF XY:
0.000946
AC XY:
677
AN XY:
715824
show subpopulations
Gnomad4 AFR exome
AF:
0.00393
Gnomad4 AMR exome
AF:
0.00208
Gnomad4 ASJ exome
AF:
0.00917
Gnomad4 EAS exome
AF:
0.0000517
Gnomad4 SAS exome
AF:
0.000546
Gnomad4 FIN exome
AF:
0.0000395
Gnomad4 NFE exome
AF:
0.000633
Gnomad4 OTH exome
AF:
0.00154
GnomAD4 genome
AF:
0.00176
AC:
268
AN:
152340
Hom.:
2
Cov.:
34
AF XY:
0.00142
AC XY:
106
AN XY:
74488
show subpopulations
Gnomad4 AFR
AF:
0.00325
Gnomad4 AMR
AF:
0.00163
Gnomad4 ASJ
AF:
0.0101
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.000207
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000926
Gnomad4 OTH
AF:
0.000946
Alfa
AF:
0.00177
Hom.:
0
Bravo
AF:
0.00202
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not provided Benign:3
Likely benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenJun 01, 2023COL6A1: BP4, BP7 -
Likely benign, criteria provided, single submitternot providedBreakthrough Genomics, Breakthrough Genomics-- -
Benign, criteria provided, single submitterclinical testingGeneDxApr 20, 2020- -
not specified Benign:1
Likely benign, criteria provided, single submitterclinical testingEurofins Ntd Llc (ga)May 04, 2015- -
Bethlem myopathy 1A Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 04, 2024- -
Collagen 6-related myopathy Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 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
-0.85
CADD
Benign
0.33
DANN
Benign
0.50

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs138976133; hg19: chr21-47422285; COSMIC: COSV100720350; COSMIC: COSV100720350; API