rs147219060

Variant names:

• chr21-46002281-G-A
• rs147219060
• NM_001848.3:c.2130G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46002281-G-A
• chr21-46002281-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.2130G>A​(p.Thr710Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00381 in 1,597,108 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0039 (31 hom.)
• Consequence: COL6A1 NM_001848.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.49
• 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=-0.42).
• BP6: Variant 21-46002281-G-A is Benign according to our data. Variant chr21-46002281-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93848.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.49 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0029 (442/152342) while in subpopulation SAS AF = 0.0122 (59/4832). AF 95% confidence interval is 0.00972. There are 3 homozygotes in GnomAd4. There are 234 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.2130G>A	p.Thr710Thr	synonymous	Exon 32 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.2130G>A	p.Thr710Thr	synonymous	Exon 32 of 35	ENSP00000355180.3	P12109
	COL6A1	ENST00000498614.5	TSL:1	n.364G>A		non_coding_transcript_exon	Exon 3 of 6
	COL6A1	ENST00000612273.2	TSL:5	c.255G>A	p.Thr85Thr	synonymous	Exon 3 of 7	ENSP00000483630.2	A0A087X0S5

Frequencies

GnomAD3 genomes AF: 0.00292 AC: 445 AN: 152224 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000651

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00360

Gnomad ASJ AF: 0.00403

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0126

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.00391

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00397 AC: 836 AN: 210700 AF XY: 0.00490

Gnomad AFR exome AF: 0.000549

Gnomad AMR exome AF: 0.00144

Gnomad ASJ exome AF: 0.00272

Gnomad EAS exome AF: 0.000126

Gnomad FIN exome AF: 0.000949

Gnomad NFE exome AF: 0.00404

Gnomad OTH exome AF: 0.00432

GnomAD4 exome AF: 0.00391 AC: 5646 AN: 1444766 Hom.: 31 Cov.: 35 AF XY: 0.00432 AC XY: 3104 AN XY: 717814

African (AFR) AF: 0.000600 AC: 20 AN: 33312

American (AMR) AF: 0.00153 AC: 65 AN: 42434

Ashkenazi Jewish (ASJ) AF: 0.00295 AC: 76 AN: 25758

East Asian (EAS) AF: 0.000231 AC: 9 AN: 39034

South Asian (SAS) AF: 0.0130 AC: 1097 AN: 84208

European-Finnish (FIN) AF: 0.00143 AC: 69 AN: 48102

Middle Eastern (MID) AF: 0.00911 AC: 52 AN: 5708

European-Non Finnish (NFE) AF: 0.00368 AC: 4071 AN: 1106394

Other (OTH) AF: 0.00313 AC: 187 AN: 59816

GnomAD4 genome AF: 0.00290 AC: 442 AN: 152342 Hom.: 3 Cov.: 34 AF XY: 0.00314 AC XY: 234 AN XY: 74490

African (AFR) AF: 0.000649 AC: 27 AN: 41580

American (AMR) AF: 0.00359 AC: 55 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.00403 AC: 14 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.0122 AC: 59 AN: 4832

European-Finnish (FIN) AF: 0.000659 AC: 7 AN: 10630

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.00391 AC: 266 AN: 68016

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00407 Hom.: 0

Bravo AF: 0.00258

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
CADD	Benign	4.1
DANN	Benign	0.73
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism

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: rs147219060; hg19: chr21-47422195;