21-46124919-C-T

Variant names:

• chr21-46124919-C-T
• rs142709940
• NM_001849.4:c.1769C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS2

The NM_001849.4(COL6A2):​c.1769C>T​(p.Thr590Met) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00246 in 1,612,876 control chromosomes in the GnomAD database, including 9 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T590K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0025 (9 hom.)
• Consequence: COL6A2 NM_001849.4 missense, splice_region
• Scores: Splicing: ADA: 0.6823
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 6.25
• 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, 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.077075034).
• BP6: Variant 21-46124919-C-T is Benign according to our data. Variant chr21-46124919-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 9 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.1769C>T	p.Thr590Met	missense splice_region	Exon 23 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1769C>T	p.Thr590Met	missense splice_region	Exon 23 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.1769C>T	p.Thr590Met	missense splice_region	Exon 23 of 28	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1769C>T	p.Thr590Met	missense splice_region	Exon 23 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1769C>T	p.Thr590Met	missense splice_region	Exon 23 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.1964C>T	p.Thr655Met	missense splice_region	Exon 23 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00168 AC: 256 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000830

Gnomad FIN AF: 0.00122

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00288

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.00187 AC: 467 AN: 250244 AF XY: 0.00174

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.000299

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00143

Gnomad NFE exome AF: 0.00262

Gnomad OTH exome AF: 0.00197

GnomAD4 exome AF: 0.00254 AC: 3708 AN: 1460548 Hom.: 9 Cov.: 34 AF XY: 0.00248 AC XY: 1804 AN XY: 726582

African (AFR) AF: 0.000538 AC: 18 AN: 33480

American (AMR) AF: 0.00219 AC: 98 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000344 AC: 9 AN: 26136

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.000916 AC: 79 AN: 86258

European-Finnish (FIN) AF: 0.00178 AC: 93 AN: 52162

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00295 AC: 3284 AN: 1111948

Other (OTH) AF: 0.00199 AC: 120 AN: 60380

GnomAD4 genome AF: 0.00168 AC: 256 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.00175 AC XY: 130 AN XY: 74486

African (AFR) AF: 0.000601 AC: 25 AN: 41574

American (AMR) AF: 0.00111 AC: 17 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000830 AC: 4 AN: 4818

European-Finnish (FIN) AF: 0.00122 AC: 13 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00288 AC: 196 AN: 68036

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.00245 Hom.: 23

Bravo AF: 0.00160

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00165 AC: 200

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00251

EpiControl AF: 0.00267

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	COL6A2-related disorder (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Myosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.016	T
BayesDel_noAF	Pathogenic	0.21
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.84	D
MetaRNN	Benign	0.077	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.71
Sift	Benign	0.034	D
Sift4G	Uncertain	0.029	D
Polyphen		1.0	D
Vest4		0.74
MVP		0.98
MPC		0.62
ClinPred		0.039	T
GERP RS		4.1
Varity_R		0.21
gMVP		0.56
Mutation Taster		=27/73	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.68
dbscSNV1_RF	Benign	0.64
SpliceAI score (max)		0.14		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: rs142709940; hg19: chr21-47544833; COSMIC: COSV56005553;