rs141703710

Variant names:

• chr21-46112179-G-A
• rs141703710
• NM_001849.4:c.316G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.316G>A​(p.Glu106Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,612,984 control chromosomes in the GnomAD database, including 128 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0069 (9 hom., cov: 32)
  • Exomes 𝑓: 0.012 (119 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 1.48
• Publications: 14 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

LOC124905043 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009793192).
• BP6: Variant 21-46112179-G-A is Benign according to our data. Variant chr21-46112179-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93953.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00685 (1044/152312) while in subpopulation NFE AF = 0.0121 (826/68018). AF 95% confidence interval is 0.0115. There are 9 homozygotes in GnomAd4. There are 463 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 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.316G>A	p.Glu106Lys	missense	Exon 3 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.316G>A	p.Glu106Lys	missense	Exon 3 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.316G>A	p.Glu106Lys	missense	Exon 3 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.316G>A	p.Glu106Lys	missense	Exon 3 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.316G>A	p.Glu106Lys	missense	Exon 3 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.316G>A	p.Glu106Lys	missense	Exon 3 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00686 AC: 1044 AN: 152194 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00244

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00386

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00665 AC: 1666 AN: 250404 AF XY: 0.00688

Gnomad AFR exome AF: 0.00204

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00592

Gnomad NFE exome AF: 0.0123

Gnomad OTH exome AF: 0.00621

GnomAD4 exome AF: 0.0118 AC: 17177 AN: 1460672 Hom.: 119 Cov.: 33 AF XY: 0.0114 AC XY: 8261 AN XY: 726630

African (AFR) AF: 0.00212 AC: 71 AN: 33480

American (AMR) AF: 0.00201 AC: 90 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000278 AC: 24 AN: 86258

European-Finnish (FIN) AF: 0.00496 AC: 259 AN: 52214

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

European-Non Finnish (NFE) AF: 0.0146 AC: 16235 AN: 1112008

Other (OTH) AF: 0.00821 AC: 496 AN: 60384

GnomAD4 genome AF: 0.00685 AC: 1044 AN: 152312 Hom.: 9 Cov.: 32 AF XY: 0.00622 AC XY: 463 AN XY: 74468

African (AFR) AF: 0.00243 AC: 101 AN: 41572

American (AMR) AF: 0.00405 AC: 62 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

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

European-Finnish (FIN) AF: 0.00386 AC: 41 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0121 AC: 826 AN: 68018

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.0105 Hom.: 23

Bravo AF: 0.00697

TwinsUK AF: 0.00620 AC: 23

ALSPAC AF: 0.00960 AC: 37

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0105 AC: 90

ExAC AF: 0.00706 AC: 857

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0117

EpiControl AF: 0.0115

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not provided (6)
-	-	5	not specified (5)
-	-	2	Bethlem myopathy 1A (2)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	Ullrich congenital muscular dystrophy 1A;C1850671:Myosclerosis;CN029274:Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.018
Eigen_PC	Benign	0.080
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.84	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.5
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.28
Sift	Benign	0.49	T
Sift4G	Benign	0.84	T
Polyphen		0.83	P
Vest4		0.70
MVP		0.73
MPC		0.15
ClinPred		0.016	T
GERP RS		4.3
Varity_R		0.19
gMVP		0.57
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs141703710; hg19: chr21-47532093;