21-46132243-G-T

Variant names:

• chr21-46132243-G-T
• rs111341650
• NM_001849.4:c.2751G>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6 BP7 BS2

The NM_001849.4(COL6A2):​c.2751G>T​(p.Val917Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00116 in 1,603,320 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. V917V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00073 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0012 (6 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• Conservation: PhyloP100: 1.53
• Publications: 1 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 21-46132243-G-T is Benign according to our data. Variant chr21-46132243-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 196117.
• BP7: Synonymous conserved (PhyloP=1.53 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.2751G>T	p.Val917Val	synonymous	Exon 28 of 28	NP_001840.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2751G>T	p.Val917Val	synonymous	Exon 28 of 28	ENSP00000300527.4
	COL6A2	ENST00000857098.1		c.2946G>T	p.Val982Val	synonymous	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2913G>T	p.Val971Val	synonymous	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000632 AC: 145 AN: 229496 AF XY: 0.000660

Gnomad AFR exome AF: 0.0000709

Gnomad AMR exome AF: 0.000361

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000173

Gnomad NFE exome AF: 0.00124

Gnomad OTH exome AF: 0.000175

GnomAD4 exome AF: 0.00120 AC: 1742 AN: 1450976 Hom.: 6 Cov.: 34 AF XY: 0.00118 AC XY: 855 AN XY: 721584

African (AFR) AF: 0.000331 AC: 11 AN: 33264

American (AMR) AF: 0.000297 AC: 13 AN: 43816

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25938

East Asian (EAS) AF: 0.00 AC: 0 AN: 39196

South Asian (SAS) AF: 0.00 AC: 0 AN: 85252

European-Finnish (FIN) AF: 0.000204 AC: 10 AN: 49050

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.00148 AC: 1638 AN: 1108666

Other (OTH) AF: 0.00117 AC: 70 AN: 60038

GnomAD4 genome AF: 0.000729 AC: 111 AN: 152344 Hom.: 0 Cov.: 34 AF XY: 0.000779 AC XY: 58 AN XY: 74494

African (AFR) AF: 0.000216 AC: 9 AN: 41588

American (AMR) AF: 0.000654 AC: 10 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.000904 Hom.: 0

Bravo AF: 0.000672

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Myosclerosis (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	8.4
DANN	Benign	0.84
PhyloP100		1.5
Mutation Taster		=100/0	polymorphism

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: rs111341650; hg19: chr21-47552157;