rs115292913

Variant names:

• chr21-45987000-G-A
• rs115292913
• NM_001848.3:c.645G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-45987000-G-A
• chr21-45987000-G-C

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_001848.3(COL6A1):​c.645G>A​(p.Ala215Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00194 in 1,551,210 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.010 (24 hom., cov: 33)
  • Exomes 𝑓: 0.0010 (21 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -1.52
• 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):

• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• collagen 6-related myopathy

  Inheritance: SD, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 21-45987000-G-A is Benign according to our data. Variant chr21-45987000-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93883.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0102 (1547/152294) while in subpopulation AFR AF = 0.0354 (1473/41564). AF 95% confidence interval is 0.0339. There are 24 homozygotes in GnomAd4. There are 729 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 AR,AD gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.645G>A	p.Ala215Ala	synonymous	Exon 5 of 35	NP_001839.2	P12109

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.645G>A	p.Ala215Ala	synonymous	Exon 5 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000866134.1		c.564+339G>A		intron	N/A	ENSP00000536193.1
	COL6A1	ENST00000492851.1	TSL:3	n.-109G>A		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.0102 AC: 1546 AN: 152176 Hom.: 23 Cov.: 33

Gnomad AFR AF: 0.0355

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00340

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: 0.000118

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00253 AC: 389 AN: 154046 AF XY: 0.00186

Gnomad AFR exome AF: 0.0393

Gnomad AMR exome AF: 0.00181

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000503

Gnomad OTH exome AF: 0.000915

GnomAD4 exome AF: 0.00104 AC: 1458 AN: 1398916 Hom.: 21 Cov.: 34 AF XY: 0.000904 AC XY: 624 AN XY: 690320

African (AFR) AF: 0.0363 AC: 1154 AN: 31798

American (AMR) AF: 0.00200 AC: 72 AN: 35962

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25192

East Asian (EAS) AF: 0.0000556 AC: 2 AN: 36002

South Asian (SAS) AF: 0.0000629 AC: 5 AN: 79488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46608

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5696

European-Non Finnish (NFE) AF: 0.0000815 AC: 88 AN: 1080122

Other (OTH) AF: 0.00231 AC: 134 AN: 58048

GnomAD4 genome AF: 0.0102 AC: 1547 AN: 152294 Hom.: 24 Cov.: 33 AF XY: 0.00979 AC XY: 729 AN XY: 74444

African (AFR) AF: 0.0354 AC: 1473 AN: 41564

American (AMR) AF: 0.00340 AC: 52 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5166

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68030

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00368 Hom.: 6

Bravo AF: 0.0114

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	COL6A1-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.82
DANN	Benign	0.89
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs115292913; hg19: chr21-47406914;