rs140790797

chr21-46115898-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_001849.4(COL6A2):c.828G>A(p.Pro276=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000812 in 1,612,840 control chromosomes in the GnomAD database, including 1 homozygotes. 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 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000073 (1 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -1.08

Genes affected

COL6A2 (HGNC:2212): (collagen type VI alpha 2 chain) This gene encodes one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The product of this gene contains several domains similar to von Willebrand Factor type A domains. These domains have been shown to bind extracellular matrix proteins, an interaction that explains the importance of this collagen in organizing matrix components. Mutations in this gene are associated with Bethlem myopathy and Ullrich scleroatonic muscular dystrophy. Three transcript variants have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant 21-46115898-G-A is Benign according to our data. Variant chr21-46115898-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 283293.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BP7: Synonymous conserved (PhyloP=-1.08 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.828G>A	p.Pro276=	synonymous_variant	6/28	ENST00000300527.9
COL6A2	NM_058174.3	c.828G>A	p.Pro276=	synonymous_variant	6/28	ENST00000397763.6
COL6A2	NM_058175.3	c.828G>A	p.Pro276=	synonymous_variant	6/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.828G>A	p.Pro276=	synonymous_variant	6/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.828G>A	p.Pro276=	synonymous_variant	6/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.828G>A	p.Pro276=	synonymous_variant	5/27	5
COL6A2	ENST00000485591.1	n.484G>A		non_coding_transcript_exon_variant	2/7	3

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.0000843 AC: 21 AN: 249194 Hom.: 0 AF XY: 0.0000740 AC XY: 10 AN XY: 135224

Gnomad AFR exome AF: 0.000499

Gnomad AMR exome AF: 0.0000869

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000941

Gnomad NFE exome AF: 0.0000534

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000726 AC: 106 AN: 1460590 Hom.: 1 Cov.: 33 AF XY: 0.0000812 AC XY: 59 AN XY: 726598

Gnomad4 AFR exome AF: 0.000657

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.0000383

Gnomad4 NFE exome AF: 0.0000441

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152250 Hom.: 0 Cov.: 32 AF XY: 0.000161 AC XY: 12 AN XY: 74436

Gnomad4 AFR AF: 0.000385

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000204 Hom.: 0

Bravo AF: 0.000227

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000178

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

Eurofins Ntd Llc (ga)

Sep 10, 2015

- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.65
Cadd	Benign	5.9
Dann	Benign	0.73

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: rs140790797; hg19: chr21-47535812; COSMIC: COSV56000423; COSMIC: COSV56000423;