21-46132261-C-T

Variant names:

• chr21-46132261-C-T
• rs140419176
• NM_001849.4:c.2769C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001849.4(COL6A2):​c.2769C>T​(p.His923His) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00912 in 1,606,208 control chromosomes in the GnomAD database, including 83 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., cov: 34)
  • Exomes 𝑓: 0.0095 (77 hom.)
• Consequence: COL6A2 NM_001849.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.824
• Publications: 2 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, SD, 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: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 21-46132261-C-T is Benign according to our data. Variant chr21-46132261-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.824 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00573 (873/152328) while in subpopulation NFE AF = 0.00997 (678/68034). AF 95% confidence interval is 0.00934. There are 6 homozygotes in GnomAd4. There are 400 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 AD,AR,SD 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.2769C>T	p.His923His	synonymous	Exon 28 of 28	NP_001840.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2769C>T	p.His923His	synonymous	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2964C>T	p.His988His	synonymous	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2931C>T	p.His977His	synonymous	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.00574 AC: 873 AN: 152210 Hom.: 6 Cov.: 34

Gnomad AFR AF: 0.00212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00236

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00415

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00996

Gnomad OTH AF: 0.00622

GnomAD2 exomes AF: 0.00507 AC: 1198 AN: 236200 AF XY: 0.00511

Gnomad AFR exome AF: 0.00182

Gnomad AMR exome AF: 0.00204

Gnomad ASJ exome AF: 0.00472

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00312

Gnomad NFE exome AF: 0.00900

Gnomad OTH exome AF: 0.00444

GnomAD4 exome AF: 0.00947 AC: 13774 AN: 1453880 Hom.: 77 Cov.: 34 AF XY: 0.00913 AC XY: 6602 AN XY: 723356

African (AFR) AF: 0.00165 AC: 55 AN: 33354

American (AMR) AF: 0.00232 AC: 103 AN: 44328

Ashkenazi Jewish (ASJ) AF: 0.00481 AC: 125 AN: 26008

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39486

South Asian (SAS) AF: 0.000525 AC: 45 AN: 85704

European-Finnish (FIN) AF: 0.00366 AC: 178 AN: 48660

Middle Eastern (MID) AF: 0.00191 AC: 11 AN: 5758

European-Non Finnish (NFE) AF: 0.0115 AC: 12821 AN: 1110398

Other (OTH) AF: 0.00723 AC: 435 AN: 60184

GnomAD4 genome AF: 0.00573 AC: 873 AN: 152328 Hom.: 6 Cov.: 34 AF XY: 0.00537 AC XY: 400 AN XY: 74486

African (AFR) AF: 0.00212 AC: 88 AN: 41576

American (AMR) AF: 0.00235 AC: 36 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00346 AC: 12 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00415 AC: 44 AN: 10612

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00997 AC: 678 AN: 68034

Other (OTH) AF: 0.00616 AC: 13 AN: 2112

Alfa AF: 0.00635 Hom.: 1

Bravo AF: 0.00539

Asia WGS AF: 0.00173 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.1
DANN	Benign	0.84
PhyloP100		-0.82
Mutation Taster		=99/1	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: rs140419176; hg19: chr21-47552175; COSMIC: COSV52430205; COSMIC: COSV52430205;