21-46002765-G-A

Variant names:

• chr21-46002765-G-A
• rs2236487
• NM_001848.3:c.2434+55G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.2434+55G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.342 in 1,487,522 control chromosomes in the GnomAD database, including 96,005 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8288 hom., cov: 35)
  • Exomes 𝑓: 0.35 (87717 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.454
• Publications: 6 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BP6: Variant 21-46002765-G-A is Benign according to our data. Variant chr21-46002765-G-A is described in ClinVar as Benign. ClinVar VariationId is 93856.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.613 is higher than 0.05.

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.2434+55G>A		intron	N/A	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.2434+55G>A		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000498614.5	TSL:1	n.668+55G>A		intron	N/A
	COL6A1	ENST00000866134.1		c.748+55G>A		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.309 AC: 45862 AN: 148494 Hom.: 8281 Cov.: 35

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.420

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.390

Gnomad EAS AF: 0.631

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.389

Gnomad MID AF: 0.378

Gnomad NFE AF: 0.347

Gnomad OTH AF: 0.342

GnomAD4 exome AF: 0.345 AC: 462219 AN: 1338912 Hom.: 87717 AF XY: 0.348 AC XY: 232732 AN XY: 668238

African (AFR) AF: 0.107 AC: 3316 AN: 31022

American (AMR) AF: 0.521 AC: 21213 AN: 40690

Ashkenazi Jewish (ASJ) AF: 0.385 AC: 9613 AN: 24960

East Asian (EAS) AF: 0.624 AC: 23817 AN: 38174

South Asian (SAS) AF: 0.392 AC: 31654 AN: 80648

European-Finnish (FIN) AF: 0.396 AC: 17840 AN: 45024

Middle Eastern (MID) AF: 0.380 AC: 1751 AN: 4612

European-Non Finnish (NFE) AF: 0.327 AC: 333218 AN: 1018200

Other (OTH) AF: 0.356 AC: 19797 AN: 55582

GnomAD4 genome AF: 0.309 AC: 45879 AN: 148610 Hom.: 8288 Cov.: 35 AF XY: 0.314 AC XY: 22838 AN XY: 72678

African (AFR) AF: 0.122 AC: 5013 AN: 41054

American (AMR) AF: 0.427 AC: 6387 AN: 14952

Ashkenazi Jewish (ASJ) AF: 0.390 AC: 1334 AN: 3424

East Asian (EAS) AF: 0.631 AC: 3177 AN: 5032

South Asian (SAS) AF: 0.404 AC: 1901 AN: 4706

European-Finnish (FIN) AF: 0.389 AC: 4044 AN: 10384

Middle Eastern (MID) AF: 0.373 AC: 103 AN: 276

European-Non Finnish (NFE) AF: 0.347 AC: 22833 AN: 65832

Other (OTH) AF: 0.346 AC: 713 AN: 2060

Alfa AF: 0.302 Hom.: 739

Bravo AF: 0.302

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	3.6
DANN	Benign	0.73
PhyloP100		0.45
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2236487; hg19: chr21-47422679; COSMIC: COSV107450283; COSMIC: COSV107450283;