rs374384263

Variant names:

• chr21-46132290-G-A
• rs374384263
• NM_001849.4:c.2798G>A

Your query was ambiguous. Multiple possible variants found:

• chr21-46132290-G-A
• chr21-46132290-G-T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BP6

The NM_001849.4(COL6A2):​c.2798G>A​(p.Arg933His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,606,564 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R933G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• Conservation: PhyloP100: -0.905
• 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, SD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AD, AR 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: 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.18448046).
• BP6: Variant 21-46132290-G-A is Benign according to our data. Variant chr21-46132290-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 283689.

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.2798G>A	p.Arg933His	missense	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.2798G>A	p.Arg933His	missense	Exon 28 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000857098.1		c.2993G>A	p.Arg998His	missense	Exon 28 of 28	ENSP00000527157.1
	COL6A2	ENST00000857103.1		c.2960G>A	p.Arg987His	missense	Exon 28 of 28	ENSP00000527162.1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152174 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000159 AC: 38 AN: 238826 AF XY: 0.000160

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000395

Gnomad FIN exome AF: 0.0000604

Gnomad NFE exome AF: 0.000128

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000134 AC: 195 AN: 1454272 Hom.: 0 Cov.: 34 AF XY: 0.000141 AC XY: 102 AN XY: 723720

African (AFR) AF: 0.0000598 AC: 2 AN: 33420

American (AMR) AF: 0.000247 AC: 11 AN: 44550

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26038

East Asian (EAS) AF: 0.000505 AC: 20 AN: 39636

South Asian (SAS) AF: 0.000186 AC: 16 AN: 86002

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47328

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5760

European-Non Finnish (NFE) AF: 0.000111 AC: 123 AN: 1111274

Other (OTH) AF: 0.000348 AC: 21 AN: 60264

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152292 Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 9 AN XY: 74474

African (AFR) AF: 0.0000241 AC: 1 AN: 41574

American (AMR) AF: 0.000196 AC: 3 AN: 15288

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.0000851 Hom.: 0

Bravo AF: 0.000151

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ExAC AF: 0.000141 AC: 17

Asia WGS AF: 0.00693 AC: 24 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000297

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not provided (3)
-	1	1	Collagen 6-related myopathy (2)
-	-	1	Bethlem myopathy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	9.5
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Benign	-0.56
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.82	T
M_CAP	Uncertain	0.16	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.58	T
MutationAssessor	Benign	1.4	L
PhyloP100		-0.91
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-2.0	N
REVEL	Benign	0.25
Sift	Uncertain	0.019	D
Sift4G	Uncertain	0.035	D
Polyphen		0.98	D
Vest4		0.23
MVP		0.86
MPC		0.42
ClinPred		0.048	T
GERP RS		1.6
Varity_R		0.055
gMVP		0.60
Mutation Taster		=90/10	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: rs374384263; hg19: chr21-47552204;