rs878854362

Positions:

• chr21-46116677-G-T
• chr21-46116677-G-A
• chr21-46116677-G-C

Variant summary

Our verdict is Pathogenic. Variant got 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 same amino acid change has been previously reported as Pathogenicin 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

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]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius 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. Variant chr21-46116677-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	9/28	ENST00000300527.9
COL6A2	NM_058174.3	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	9/28	ENST00000397763.6
COL6A2	NM_058175.3	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	9/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	9/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	9/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.954G>T	p.Lys318Asn	missense_variant, splice_region_variant	8/27	5
COL6A2	ENST00000485591.1	n.610G>T		splice_region_variant, non_coding_transcript_exon_variant	5/7	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

Likely pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Apr 22, 2024	- -
Likely pathogenic, criteria provided, single submitter	research	Center for Genetic Medicine Research, Children's National Medical Center	Dec 01, 2015	- -

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
MutationTaster	Benign	1.0	D;D;D;D;D
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

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

Publications

LitVar

Other links and lift over

dbSNP: rs878854362; hg19: chr21-47536591;