21-46111481-T-C

Variant names:

• chr21-46111481-T-C
• NM_001849.4:c.5T>C

Variant summary

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

The NM_001849.4(COL6A2):​c.5T>C​(p.Leu2Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: COL6A2 NM_001849.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.165
• 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 2 ACMG points.

• 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.5T>C	p.Leu2Pro	missense_variant	Exon 2 of 28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.5T>C	p.Leu2Pro	missense_variant	Exon 2 of 28		NP_478054.2
COL6A2	NM_058175.3	c.5T>C	p.Leu2Pro	missense_variant	Exon 2 of 28		NP_478055.2
LOC124905043	XR_007067910.1	n.551A>G		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.5T>C	p.Leu2Pro	missense_variant	Exon 2 of 28	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.5T>C	p.Leu2Pro	missense_variant	Exon 2 of 28	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.5T>C	p.Leu2Pro	missense_variant	Exon 1 of 27	5		ENSP00000387115.1
COL6A2	ENST00000436769.5	c.5T>C	p.Leu2Pro	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

Inborn genetic diseases Uncertain:1

Mar 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.5T>C (p.L2P) alteration is located in exon 2 (coding exon 1) of the COL6A2 gene. This alteration results from a T to C substitution at nucleotide position 5, causing the leucine (L) at amino acid position 2 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	21
DANN	Uncertain	0.98
DEOGEN2	Benign	0.25	T;.;T;.;.
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.18	T;T;T;.;T
M_CAP	Pathogenic	0.48	D
MetaRNN	Uncertain	0.47	T;T;T;T;T
MetaSVM	Uncertain	-0.038	T
MutationAssessor	Benign	2.0	M;M;.;M;M
PhyloP100		0.17
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-2.2	N;N;N;N;N
REVEL	Uncertain	0.45
Sift	Uncertain	0.0070	D;D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D;D
Polyphen		0.91	P;D;.;D;D
Vest4		0.31
MutPred		0.35		Gain of catalytic residue at L2 (P = 0.0097);Gain of catalytic residue at L2 (P = 0.0097);Gain of catalytic residue at L2 (P = 0.0097);Gain of catalytic residue at L2 (P = 0.0097);Gain of catalytic residue at L2 (P = 0.0097);
MVP		0.98
MPC		0.71
ClinPred		0.44	T
GERP RS		3.0
PromoterAI		0.010	Neutral
Varity_R		0.40
gMVP		0.84
Mutation Taster		=72/28	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: chr21-47531395;