rs1339553173

Positions:

• chr2-237344762-C-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BP6

The NM_004369.4(COL6A3):​c.7256G>C​(p.Gly2419Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,449,360 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL6A3 NM_004369.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.644

Genes affected

COL6A3 (HGNC:2213): (collagen type VI alpha 3 chain) This gene encodes the alpha-3 chain, one of the three alpha chains of type VI collagen, a beaded filament collagen found in most connective tissues. The alpha-3 chain of type VI collagen is much larger than the alpha-1 and -2 chains. This difference in size is largely due to an increase in the number of subdomains, similar to von Willebrand Factor type A domains, that are found in the amino terminal globular domain of all the alpha chains. 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 the type VI collagen genes are associated with Bethlem myopathy, a rare autosomal dominant proximal myopathy with early childhood onset. Mutations in this gene are also a cause of Ullrich congenital muscular dystrophy, also referred to as Ullrich scleroatonic muscular dystrophy, an autosomal recessive congenital myopathy that is more severe than Bethlem myopathy. Multiple transcript variants have been identified, but the full-length nature of only some of these variants has been described. [provided by RefSeq, Jun 2009]

COL6A3 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14156583).
• BP6: Variant 2-237344762-C-G is Benign according to our data. Variant chr2-237344762-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 476553.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A3	NM_004369.4	c.7256G>C	p.Gly2419Ala	missense_variant	36/44	ENST00000295550.9	NP_004360.2
COL6A3	NM_057167.4	c.6638G>C	p.Gly2213Ala	missense_variant	35/43		NP_476508.2
COL6A3	NM_057166.5	c.5435G>C	p.Gly1812Ala	missense_variant	33/41		NP_476507.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A3	ENST00000295550.9	c.7256G>C	p.Gly2419Ala	missense_variant	36/44	1	NM_004369.4	ENSP00000295550.4
COL6A3	ENST00000472056.5	c.5435G>C	p.Gly1812Ala	missense_variant	33/41	1		ENSP00000418285.1
COL6A3	ENST00000353578.9	c.6638G>C	p.Gly2213Ala	missense_variant	35/43	5		ENSP00000315873.4
COL6A3	ENST00000491769.1	n.1510G>C		non_coding_transcript_exon_variant	13/20	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000413 AC: 1 AN: 242366 Hom.: 0 AF XY: 0.00000761 AC XY: 1 AN XY: 131330

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1449360 Hom.: 0 Cov.: 34 AF XY: 0.00000417 AC XY: 3 AN XY: 720056

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000691

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	AiLife Diagnostics, AiLife Diagnostics	Jul 29, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Apr 01, 2019	- -

Bethlem myopathy 1A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 23, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	5.7
DANN	Benign	0.47
DEOGEN2	Benign	0.15	.;T;.;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.0
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T;T;T;T;.
M_CAP	Benign	0.059	D
MetaRNN	Benign	0.14	T;T;T;T;T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.0	.;N;.;.;.
PrimateAI	Benign	0.40	T
PROVEAN	Benign	0.020	N;N;N;.;N
REVEL	Benign	0.14
Sift	Benign	0.62	T;T;T;.;T
Sift4G	Benign	0.29	T;T;T;T;T
Polyphen		0.0	B;B;.;.;B
Vest4		0.16
MutPred		0.44		.;Gain of catalytic residue at G2419 (P = 0.0377);.;.;.;
MVP		0.51
MPC		0.16
ClinPred		0.022	T
GERP RS		1.7
Varity_R		0.037
gMVP		0.24

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

Publications

LitVar

Other links and lift over

dbSNP: rs1339553173; hg19: chr2-238253405;