rs373181368

Positions:

• chr21-46117459-G-A

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001849.4(COL6A2):​c.1053+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000757 in 1,612,528 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000077 (0 hom.)
• Consequence: COL6A2 NM_001849.4 splice_region, intron
• Scores: Splicing: ADA: 0.00001721
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -2.22

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]

COL6A2 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1053+6G>A		splice_region_variant, intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1053+6G>A		splice_region_variant, intron_variant			NP_478054.2
COL6A2	NM_058175.3	c.1053+6G>A		splice_region_variant, intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1053+6G>A		splice_region_variant, intron_variant		1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1053+6G>A		splice_region_variant, intron_variant		5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1053+6G>A		splice_region_variant, intron_variant		5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.715G>A		non_coding_transcript_exon_variant	7/7	3

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152216 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

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: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000145 AC: 36 AN: 249010 Hom.: 0 AF XY: 0.0000962 AC XY: 13 AN XY: 135190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000980

Gnomad OTH exome AF: 0.000988

GnomAD4 exome AF: 0.0000774 AC: 113 AN: 1460312 Hom.: 0 Cov.: 31 AF XY: 0.0000647 AC XY: 47 AN XY: 726448

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000702

Gnomad4 OTH exome AF: 0.0000828

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152216 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74354

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000478

Alfa AF: 0.0000987 Hom.: 0

Bravo AF: 0.000125

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 24, 2023

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. ClinVar contains an entry for this variant (Variation ID: 285137). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is present in population databases (rs373181368, gnomAD 0.06%). This sequence change falls in intron 11 of the COL6A2 gene. It does not directly change the encoded amino acid sequence of the COL6A2 protein. It affects a nucleotide within the consensus splice site. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Dec 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.083
DANN	Benign	0.45

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000017
dbscSNV1_RF	Benign	0.0
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: rs373181368; hg19: chr21-47537373;