NM_001849.4:c.1671+10A>G

Variant names:

• chr21-46122947-A-G
• rs915786
• NM_001849.4:c.1671+10A>G

Variant summary

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

The NM_001849.4(COL6A2):​c.1671+10A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.818 in 1,611,788 control chromosomes in the GnomAD database, including 542,191 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.86 (56015 hom., cov: 30)
  • Exomes 𝑓: 0.81 (486176 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: -3.35
• Publications: 14 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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BP6: Variant 21-46122947-A-G is Benign according to our data. Variant chr21-46122947-A-G is described in ClinVar as Benign. ClinVar VariationId is 93914.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.939 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. 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
	COL6A2	NM_001849.4	MANE Select	c.1671+10A>G		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1671+10A>G		intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.1671+10A>G		intron	N/A	NP_478055.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1671+10A>G		intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1671+10A>G		intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000857098.1		c.1866+10A>G		intron	N/A	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.855 AC: 129896 AN: 151906 Hom.: 55951 Cov.: 30

Gnomad AFR AF: 0.947

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.796

Gnomad EAS AF: 0.883

Gnomad SAS AF: 0.644

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.750

Gnomad NFE AF: 0.818

Gnomad OTH AF: 0.874

GnomAD2 exomes AF: 0.816 AC: 203912 AN: 249962 AF XY: 0.801

Gnomad AFR exome AF: 0.949

Gnomad AMR exome AF: 0.913

Gnomad ASJ exome AF: 0.789

Gnomad EAS exome AF: 0.870

Gnomad FIN exome AF: 0.794

Gnomad NFE exome AF: 0.814

Gnomad OTH exome AF: 0.813

GnomAD4 exome AF: 0.814 AC: 1188273 AN: 1459764 Hom.: 486176 Cov.: 44 AF XY: 0.807 AC XY: 586222 AN XY: 726236

African (AFR) AF: 0.950 AC: 31812 AN: 33474

American (AMR) AF: 0.913 AC: 40812 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 20837 AN: 26128

East Asian (EAS) AF: 0.913 AC: 36221 AN: 39694

South Asian (SAS) AF: 0.632 AC: 54528 AN: 86234

European-Finnish (FIN) AF: 0.794 AC: 41578 AN: 52398

Middle Eastern (MID) AF: 0.782 AC: 4507 AN: 5766

European-Non Finnish (NFE) AF: 0.818 AC: 908726 AN: 1111006

Other (OTH) AF: 0.816 AC: 49252 AN: 60346

GnomAD4 genome AF: 0.855 AC: 130017 AN: 152024 Hom.: 56015 Cov.: 30 AF XY: 0.851 AC XY: 63210 AN XY: 74272

African (AFR) AF: 0.947 AC: 39282 AN: 41494

American (AMR) AF: 0.891 AC: 13614 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.796 AC: 2762 AN: 3472

East Asian (EAS) AF: 0.884 AC: 4530 AN: 5126

South Asian (SAS) AF: 0.642 AC: 3088 AN: 4808

European-Finnish (FIN) AF: 0.788 AC: 8327 AN: 10572

Middle Eastern (MID) AF: 0.745 AC: 219 AN: 294

European-Non Finnish (NFE) AF: 0.818 AC: 55579 AN: 67952

Other (OTH) AF: 0.874 AC: 1848 AN: 2114

Alfa AF: 0.827 Hom.: 11692

Bravo AF: 0.873

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	Bethlem myopathy 1A (2)
-	-	2	Myosclerosis (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)
-	-	1	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	0.064
DANN	Benign	0.15
PhyloP100		-3.4
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs915786; hg19: chr21-47542861;