rs377586358

Positions:

• chr21-46003541-G-A

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001848.3(COL6A1):​c.2615G>A​(p.Arg872Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000409 in 1,612,054 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000079 (0 hom., cov: 35)
  • Exomes 𝑓: 0.000037 (0 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 3.08

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]

ACMG classification

Verdict is Likely_benign. Variant got -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.22391674).
• BP6: Variant 21-46003541-G-A is Benign according to our data. Variant chr21-46003541-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476427.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A1	NM_001848.3	c.2615G>A	p.Arg872Gln	missense_variant	35/35	ENST00000361866.8	NP_001839.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A1	ENST00000361866.8	c.2615G>A	p.Arg872Gln	missense_variant	35/35	1	NM_001848.3	ENSP00000355180	P1

Frequencies

GnomAD3 genomes AF: 0.0000788 AC: 12 AN: 152246 Hom.: 0 Cov.: 35

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000575 AC: 14 AN: 243598 Hom.: 0 AF XY: 0.0000450 AC XY: 6 AN XY: 133264

Gnomad AFR exome AF: 0.000533

Gnomad AMR exome AF: 0.0000583

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000328

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000275

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000370 AC: 54 AN: 1459690 Hom.: 0 Cov.: 81 AF XY: 0.0000399 AC XY: 29 AN XY: 726134

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.0000332

GnomAD4 genome AF: 0.0000788 AC: 12 AN: 152364 Hom.: 0 Cov.: 35 AF XY: 0.000107 AC XY: 8 AN XY: 74506

Gnomad4 AFR AF: 0.000192

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000869

ESP6500AA AF: 0.000457 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000580 AC: 7

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Nov 11, 2021

- -

Bethlem myopathy 1A Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.66	D;T
Eigen	Benign	0.031
Eigen_PC	Benign	-0.0043
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.78	T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Uncertain	-0.18	T
MutationAssessor	Benign	1.7	L;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.67	T
PROVEAN	Uncertain	-3.2	D;.
REVEL	Uncertain	0.51
Sift	Uncertain	0.0040	D;.
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.91	P;.
Vest4		0.34
MVP		0.64
MPC		0.85
ClinPred		0.17	T
GERP RS		4.0
Varity_R		0.28
gMVP		0.65

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

Other links and lift over

dbSNP: rs377586358; hg19: chr21-47423455; COSMIC: COSV62614670; COSMIC: COSV62614670;