chr21-46120507-T-C

Variant names:

• chr21-46120507-T-C
• rs73159701
• NM_001849.4:c.1333-8T>C

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.1333-8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.214 in 1,512,874 control chromosomes in the GnomAD database, including 37,201 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.18 (2760 hom., cov: 34)
  • Exomes 𝑓: 0.22 (34441 hom.)
• Consequence: COL6A2 NM_001849.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001797
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.804
• Publications: 7 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=-0.75).
• BP6: Variant 21-46120507-T-C is Benign according to our data. Variant chr21-46120507-T-C is described in ClinVar as Benign. ClinVar VariationId is 93906.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.295 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.1333-8T>C		splice_region intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1333-8T>C		splice_region intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.1333-8T>C		splice_region 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.1333-8T>C		splice_region intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1333-8T>C		splice_region intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000857098.1		c.1520T>C	p.Phe507Ser	missense	Exon 16 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.179 AC: 27138 AN: 151980 Hom.: 2759 Cov.: 34

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.169

Gnomad ASJ AF: 0.186

Gnomad EAS AF: 0.307

Gnomad SAS AF: 0.164

Gnomad FIN AF: 0.0754

Gnomad MID AF: 0.226

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.213

GnomAD2 exomes AF: 0.179 AC: 20432 AN: 114234 AF XY: 0.181

Gnomad AFR exome AF: 0.121

Gnomad AMR exome AF: 0.155

Gnomad ASJ exome AF: 0.178

Gnomad EAS exome AF: 0.291

Gnomad FIN exome AF: 0.0747

Gnomad NFE exome AF: 0.219

Gnomad OTH exome AF: 0.190

GnomAD4 exome AF: 0.217 AC: 295954 AN: 1360774 Hom.: 34441 Cov.: 32 AF XY: 0.216 AC XY: 144602 AN XY: 670540

African (AFR) AF: 0.115 AC: 3391 AN: 29522

American (AMR) AF: 0.154 AC: 4211 AN: 27320

Ashkenazi Jewish (ASJ) AF: 0.187 AC: 4286 AN: 22882

East Asian (EAS) AF: 0.385 AC: 13353 AN: 34682

South Asian (SAS) AF: 0.151 AC: 11261 AN: 74554

European-Finnish (FIN) AF: 0.0821 AC: 3865 AN: 47068

Middle Eastern (MID) AF: 0.233 AC: 1132 AN: 4856

European-Non Finnish (NFE) AF: 0.228 AC: 242524 AN: 1063930

Other (OTH) AF: 0.213 AC: 11931 AN: 55960

GnomAD4 genome AF: 0.178 AC: 27144 AN: 152100 Hom.: 2760 Cov.: 34 AF XY: 0.173 AC XY: 12849 AN XY: 74364

African (AFR) AF: 0.125 AC: 5189 AN: 41524

American (AMR) AF: 0.169 AC: 2584 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 646 AN: 3468

East Asian (EAS) AF: 0.307 AC: 1586 AN: 5162

South Asian (SAS) AF: 0.163 AC: 786 AN: 4814

European-Finnish (FIN) AF: 0.0754 AC: 800 AN: 10614

Middle Eastern (MID) AF: 0.218 AC: 64 AN: 294

European-Non Finnish (NFE) AF: 0.220 AC: 14907 AN: 67910

Other (OTH) AF: 0.213 AC: 449 AN: 2112

Alfa AF: 0.189 Hom.: 963

Bravo AF: 0.185

Asia WGS AF: 0.220 AC: 767 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	3.4
DANN	Benign	0.73
PhyloP100		-0.80
PromoterAI		0.0022	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00018
dbscSNV1_RF	Benign	0.016
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: rs73159701; hg19: chr21-47540421; COSMIC: COSV56014168; COSMIC: COSV56014168;