rs1555873523

Variant names:

• chr21-46117898-G-T
• rs1555873523
• NM_001849.4:c.1078G>T

Variant summary

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

The NM_001849.4(COL6A2):​c.1078G>T​(p.Ala360Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A360G) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.71
• 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 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 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.1078G>T	p.Ala360Ser	missense_variant	Exon 12 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1078G>T	p.Ala360Ser	missense_variant	Exon 12 of 28		NP_478054.2
COL6A2	NM_058175.3	c.1078G>T	p.Ala360Ser	missense_variant	Exon 12 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1078G>T	p.Ala360Ser	missense_variant	Exon 12 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1078G>T	p.Ala360Ser	missense_variant	Exon 12 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1078G>T	p.Ala360Ser	missense_variant	Exon 11 of 27	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Feb 15, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a COL6A2-related disease. This sequence change replaces alanine with serine at codon 360 of the COL6A2 protein (p.Ala360Ser). The alanine residue is moderately conserved and there is a moderate physicochemical difference between alanine and serine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.;.;.
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D;D;.;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.72	D;D;D;D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Benign	0.64	N;N;N;N
PhyloP100		4.7
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.58	N;N;N;N
REVEL	Uncertain	0.30
Sift	Benign	0.61	T;T;T;T
Sift4G	Benign	0.43	T;T;T;T
Polyphen		1.0	D;P;P;D
Vest4		0.52
MutPred		0.45		Gain of phosphorylation at A360 (P = 0.0043);Gain of phosphorylation at A360 (P = 0.0043);Gain of phosphorylation at A360 (P = 0.0043);Gain of phosphorylation at A360 (P = 0.0043);
MVP		0.93
MPC		0.58
ClinPred		0.83	D
GERP RS		4.5
Varity_R		0.13
gMVP		0.079
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs1555873523; hg19: chr21-47537812;