21-46114062-C-A

Variant names:

• chr21-46114062-C-A
• rs760263812
• NM_001849.4:c.790C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001849.4(COL6A2):​c.790C>A​(p.Arg264Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,178 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R264H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.783
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001849.4
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.790C>A	p.Arg264Ser	missense_variant	Exon 5 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.790C>A	p.Arg264Ser	missense_variant	Exon 5 of 28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.790C>A	p.Arg264Ser	missense_variant	Exon 5 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.790C>A	p.Arg264Ser	missense_variant	Exon 5 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.790C>A	p.Arg264Ser	missense_variant	Exon 5 of 28	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000409416.6	c.790C>A	p.Arg264Ser	missense_variant	Exon 4 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.446C>A		non_coding_transcript_exon_variant	Exon 1 of 7	3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461178 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 726940

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53058

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111694

Other (OTH) AF: 0.00 AC: 0 AN: 60380

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Uncertain	24
DANN	Benign	0.95
DEOGEN2	Uncertain	0.42	T;.;.;.
Eigen	Benign	0.030
Eigen_PC	Benign	0.093
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Uncertain	0.86	D;D;.;D
M_CAP	Pathogenic	0.47	D
MetaRNN	Uncertain	0.71	D;D;D;D
MetaSVM	Pathogenic	0.81	D
MutationAssessor	Benign	1.2	L;L;L;L
PhyloP100		0.78
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.4	N;N;N;N
REVEL	Pathogenic	0.73
Sift	Benign	0.21	T;T;T;T
Sift4G	Benign	0.17	T;T;T;T
Polyphen		0.99	D;B;B;P
Vest4		0.70
MutPred		0.42		Loss of MoRF binding (P = 0.0251);Loss of MoRF binding (P = 0.0251);Loss of MoRF binding (P = 0.0251);Loss of MoRF binding (P = 0.0251);
MVP		0.99
MPC		0.59
ClinPred		0.90	D
GERP RS		3.5
Varity_R		0.30
gMVP		0.69
Mutation Taster		=46/54	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs760263812; hg19: chr21-47533976;