21-46116377-G-T

Variant names:

• chr21-46116377-G-T
• rs886042705
• NM_001849.4:c.901G>T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PM5 PP3_Strong PP5_Moderate

The NM_001849.4(COL6A2):​c.901G>T​(p.Gly301Cys) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G301D) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: COL6A2 NM_001849.4 missense, splice_region
• Scores: Splicing: ADA: 0.7325
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.11

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 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-46116378-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.996
• PP5: Variant 21-46116377-G-T is Pathogenic according to our data. Variant chr21-46116377-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 803641.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	Exon 8 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	Exon 8 of 28		NP_478054.2
COL6A2	NM_058175.3	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	Exon 8 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	Exon 8 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	Exon 8 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.901G>T	p.Gly301Cys	missense_variant, splice_region_variant	Exon 7 of 27	5		ENSP00000387115.1
COL6A2	ENST00000485591.1	n.557G>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 4 of 7	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Pathogenic:1

May 28, 2019

Mendelics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.89	D;.;.;.
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;.;D
M_CAP	Pathogenic	0.87	D
MetaRNN	Pathogenic	1.0	D;D;D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.4	H;H;H;H
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-7.2	D;D;D;D
REVEL	Pathogenic	0.91
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0020	D;D;D;D
Polyphen		1.0	D;D;D;D
Vest4		0.97
MutPred		0.99		Loss of catalytic residue at P297 (P = 0.0722);Loss of catalytic residue at P297 (P = 0.0722);Loss of catalytic residue at P297 (P = 0.0722);Loss of catalytic residue at P297 (P = 0.0722);
MVP		0.98
MPC		0.63
ClinPred		1.0	D
GERP RS		4.1
Varity_R		0.94
gMVP		0.99

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.73
dbscSNV1_RF	Pathogenic	0.76
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs886042705; hg19: chr21-47536291;