21-46111496-C-T

Variant names:

• chr21-46111496-C-T
• NM_001849.4:c.20C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001849.4(COL6A2):​c.20C>T​(p.Ser7Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S7S) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 30)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.319
• 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

LOC124905043 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.17150205).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.20C>T	p.Ser7Phe	missense_variant	Exon 2 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.20C>T	p.Ser7Phe	missense_variant	Exon 2 of 28		NP_478054.2
COL6A2	NM_058175.3	c.20C>T	p.Ser7Phe	missense_variant	Exon 2 of 28		NP_478055.2
LOC124905043	XR_007067910.1	n.536G>A		non_coding_transcript_exon_variant	Exon 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.20C>T	p.Ser7Phe	missense_variant	Exon 2 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.20C>T	p.Ser7Phe	missense_variant	Exon 2 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.20C>T	p.Ser7Phe	missense_variant	Exon 1 of 27	5		ENSP00000387115.1
COL6A2	ENST00000436769.5	c.20C>T	p.Ser7Phe	missense_variant	Exon 2 of 3	2		ENSP00000390418.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 30

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Oct 30, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 7 of the COL6A2 protein (p.Ser7Phe). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt COL6A2 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	3.0
DANN	Benign	0.28
DEOGEN2	Benign	0.14	T;.;T;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.030	N
LIST_S2	Benign	0.70	T;T;T;.;T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.17	T;T;T;T;T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.5	L;L;.;L;L
PhyloP100		-0.32
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.37	N;N;N;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.15	T;D;T;D;T
Sift4G	Uncertain	0.025	D;D;T;D;D
Polyphen		0.047	B;B;.;B;B
Vest4		0.32
MutPred		0.40		Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);Loss of disorder (P = 0.0267);
MVP		0.79
MPC		0.16
ClinPred		0.088	T
GERP RS		-1.5
PromoterAI		0.015	Neutral
Varity_R		0.11
gMVP		0.17
Mutation Taster		=91/9	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

hg19: chr21-47531410; COSMIC: COSV56000594; COSMIC: COSV56000594;