NM_001849.4:c.954G>C

Variant names:

• chr21-46116677-G-C
• rs878854362
• NM_001849.4:c.954G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_001849.4(COL6A2):​c.954G>C​(p.Lys318Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Synonymous variant affecting the same amino acid position (i.e. K318K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense, splice_region
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.63
• 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, 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: Likely_pathogenic. The variant received 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 21-46116677-G-C is Pathogenic according to our data. Variant chr21-46116677-G-C is described in ClinVar as Pathogenic. ClinVar VariationId is 1073867.Status of the report is criteria_provided_single_submitter, 1 stars.

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.954G>C	p.Lys318Asn	missense splice_region	Exon 9 of 28	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.954G>C	p.Lys318Asn	missense splice_region	Exon 9 of 28	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.954G>C	p.Lys318Asn	missense splice_region	Exon 9 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.954G>C	p.Lys318Asn	missense splice_region	Exon 9 of 28	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.954G>C	p.Lys318Asn	missense splice_region	Exon 9 of 28	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000857098.1		c.954G>C	p.Lys318Asn	missense splice_region	Exon 9 of 28	ENSP00000527157.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

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
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	38
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D
Eigen	Uncertain	0.63
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.64	D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		7.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.48
MutPred		0.46		Loss of ubiquitination at K318 (P = 0.0074)
MVP		0.98
MPC		0.64
ClinPred		0.99	D
GERP RS		5.0
Varity_R		0.71
gMVP		0.80
Mutation Taster		=0/100	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.88		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.65		Position offset: 13
DS_DL_spliceai		0.88		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs878854362; hg19: chr21-47536591;