rs1288520983

Variant names:

• chr21-46111447-C-A
• rs1288520983
• NM_001849.4:c.-27-3C>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46111447-C-A
• chr21-46111447-C-G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001849.4(COL6A2):​c.-27-3C>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 0.000000707 in 1,414,924 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 splice_region, intron
• Scores: Splicing: ADA: 0.9925
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.266
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

LOC124905043 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.-27-3C>A		splice_region_variant, intron_variant	Intron 1 of 27	ENST00000300527.9	NP_001840.3
LOC124905043	XR_007067910.1	n.585G>T		non_coding_transcript_exon_variant	Exon 1 of 2
COL6A2	NM_058174.3	c.-27-3C>A		splice_region_variant, intron_variant	Intron 1 of 27		NP_478054.2
COL6A2	NM_058175.3	c.-27-3C>A		splice_region_variant, intron_variant	Intron 1 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.-27-3C>A		splice_region_variant, intron_variant	Intron 1 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.-27-3C>A		splice_region_variant, intron_variant	Intron 1 of 27	5		ENSP00000380870.1
COL6A2	ENST00000436769.5	c.-27-3C>A		splice_region_variant, intron_variant	Intron 1 of 2	2		ENSP00000390418.1
COL6A2	ENST00000409416.6	c.-30C>A		upstream_gene_variant		5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414924 Hom.: 0 Cov.: 27 AF XY: 0.00000142 AC XY: 1 AN XY: 704646

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 32560

American (AMR) AF: 0.00 AC: 0 AN: 44332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25760

East Asian (EAS) AF: 0.00 AC: 0 AN: 39222

South Asian (SAS) AF: 0.00 AC: 0 AN: 84978

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51962

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5448

European-Non Finnish (NFE) AF: 9.33e-7 AC: 1 AN: 1072066

Other (OTH) AF: 0.00 AC: 0 AN: 58596

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	17
DANN	Benign	0.78
PhyloP100		-0.27
PromoterAI		0.015	Neutral

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.86
SpliceAI score (max)		0.23		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.23		Position offset: 11

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1288520983; hg19: chr21-47531361;