21-45986696-G-GCC

Variant names:

• chr21-45986696-G-GCC
• rs111710378
• NM_001848.3:c.588+18_588+19dupCC

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_001848.3(COL6A1):​c.588+18_588+19dupCC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000142 in 1,544,432 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000079 (0 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.45
• Publications: 2 publications found

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]

COL6A1 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

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

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 21-45986696-G-GCC is Benign according to our data. Variant chr21-45986696-G-GCC is described in ClinVar as Benign. ClinVar VariationId is 1563931.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0000725 (11/151812) while in subpopulation AFR AF = 0.000242 (10/41316). AF 95% confidence interval is 0.000131. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.588+18_588+19dupCC		intron	N/A	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.588+11_588+12insCC		intron	N/A	ENSP00000355180.3

Frequencies

GnomAD3 genomes AF: 0.0000725 AC: 11 AN: 151694 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000197

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000466 AC: 7 AN: 150210 AF XY: 0.0000502

Gnomad AFR exome AF: 0.000122

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000891

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000790 AC: 11 AN: 1392620 Hom.: 0 Cov.: 34 AF XY: 0.0000102 AC XY: 7 AN XY: 687010

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

African (AFR) AF: 0.0000954 AC: 3 AN: 31432

American (AMR) AF: 0.0000839 AC: 3 AN: 35748

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25172

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35694

South Asian (SAS) AF: 0.0000253 AC: 2 AN: 79162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43926

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5228

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078402

Other (OTH) AF: 0.00 AC: 0 AN: 57856

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000141441), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000725 AC: 11 AN: 151812 Hom.: 0 Cov.: 31 AF XY: 0.0000539 AC XY: 4 AN XY: 74198

African (AFR) AF: 0.000242 AC: 10 AN: 41316

American (AMR) AF: 0.00 AC: 0 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000197 AC: 1 AN: 5076

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67952

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 14

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Benign:1

Nov 07, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-1.5

Splicing

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

Other links and lift over

dbSNP: rs111710378; hg19: chr21-47406610;