rs535581551

Variant names:

• chr21-46126053-G-A
• rs535581551
• NM_001849.4:c.2238G>A

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Strong BP6_Moderate BP7

The ENST00000300527.9(COL6A2):​c.2238G>A​(p.Ala746Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000564 in 1,613,034 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000085 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000053 (0 hom.)
• Consequence: COL6A2 ENST00000300527.9 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.18
• Publications: 3 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 -7 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 21-46126053-G-A is Benign according to our data. Variant chr21-46126053-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 476466.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-2.18 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000300527.9. 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.2238G>A	p.Ala746Ala	synonymous	Exon 26 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.2238G>A	p.Ala746Ala	synonymous	Exon 26 of 28	NP_478054.2
	COL6A2	NM_058175.3		c.2238G>A	p.Ala746Ala	synonymous	Exon 26 of 28	NP_478055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.2238G>A	p.Ala746Ala	synonymous	Exon 26 of 28	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.2238G>A	p.Ala746Ala	synonymous	Exon 26 of 28	ENSP00000380870.1
	COL6A2	ENST00000409416.6	TSL:5	c.2238G>A	p.Ala746Ala	synonymous	Exon 25 of 27	ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0000920 AC: 14 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000997 AC: 25 AN: 250824 AF XY: 0.000118

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000376

Gnomad ASJ exome AF: 0.0000994

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000795

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000534 AC: 78 AN: 1460712 Hom.: 0 Cov.: 38 AF XY: 0.0000592 AC XY: 43 AN XY: 726672

African (AFR) AF: 0.0000896 AC: 3 AN: 33478

American (AMR) AF: 0.000224 AC: 10 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26128

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0000464 AC: 4 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52294

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000468 AC: 52 AN: 1111980

Other (OTH) AF: 0.0000828 AC: 5 AN: 60384

GnomAD4 genome AF: 0.0000853 AC: 13 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.0000940 AC XY: 7 AN XY: 74490

African (AFR) AF: 0.0000241 AC: 1 AN: 41576

American (AMR) AF: 0.000392 AC: 6 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68028

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000116 Hom.: 0

Bravo AF: 0.0000945

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.17
DANN	Benign	0.71
PhyloP100		-2.2

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: rs535581551; hg19: chr21-47545967; COSMIC: COSV56011856; COSMIC: COSV56011856;