21-46116677-G-T

Variant names:

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

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2 PP3_Strong PP5_Very_Strong

The NM_001849.4(COL6A2):​c.954G>T​(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 Likely pathogenic (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as 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: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 7.63
• Publications: 2 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: Pathogenic. The variant received 14 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-T is Pathogenic according to our data. Variant chr21-46116677-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 224657.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	Exon 9 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	Exon 9 of 28		NP_478054.2
COL6A2	NM_058175.3	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	Exon 9 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	Exon 9 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	Exon 9 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	Exon 8 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.610G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 5 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:2

Apr 22, 2024

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 01, 2015

Center for Genetic Medicine Research, Children's National Medical Center

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Pathogenic	37
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;D;.;D
M_CAP	Pathogenic	0.38	D
MetaRNN	Uncertain	0.64	D;D;D;D
MetaSVM	Uncertain	0.79	D
MutationAssessor	Uncertain	2.2	M;M;M;M
PhyloP100		7.6
PrimateAI	Uncertain	0.62	T
PROVEAN	Uncertain	-4.0	D;D;D;D
REVEL	Uncertain	0.60
Sift	Uncertain	0.0030	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.48
MutPred		0.46		Loss of ubiquitination at K318 (P = 0.0074);Loss of ubiquitination at K318 (P = 0.0074);Loss of ubiquitination at K318 (P = 0.0074);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 (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	1.0
SpliceAI score (max)		0.81		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.37		Position offset: 13
DS_DL_spliceai		0.81		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;