21-46119046-G-T

Position:

• chr21-46119046-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000300527.9(COL6A2):​c.1196G>T​(p.Ser399Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,460,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. S399N) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 35)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: COL6A2 ENST00000300527.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.444

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2015931).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1196G>T	p.Ser399Ile	missense_variant	14/28	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1196G>T	p.Ser399Ile	missense_variant	14/28	ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1196G>T	p.Ser399Ile	missense_variant	14/28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1196G>T	p.Ser399Ile	missense_variant	14/28	1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1196G>T	p.Ser399Ile	missense_variant	14/28	5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1196G>T	p.Ser399Ile	missense_variant	13/27	5		ENSP00000387115

Frequencies

GnomAD3 genomes Cov.: 35

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249272 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135318

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000579

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: 0.00000137 AC: 2 AN: 1460378 Hom.: 0 Cov.: 46 AF XY: 0.00000138 AC XY: 1 AN XY: 726502

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

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.: 35

ExAC AF: 0.00000827 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Bethlem myopathy 1A Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Sep 03, 2023

Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL6A2 protein function. 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. ClinVar contains an entry for this variant (Variation ID: 2027870). This variant has not been reported in the literature in individuals affected with COL6A2-related conditions. This variant is present in population databases (rs2839110, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with isoleucine, which is neutral and non-polar, at codon 399 of the COL6A2 protein (p.Ser399Ile). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.090	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	6.0
DANN	Benign	0.75
DEOGEN2	Benign	0.18	T;.;.;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.67	T;T;.;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.36	T
MutationAssessor	Benign	1.3	L;L;L;L
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-2.0	N;N;N;N
REVEL	Benign	0.13
Sift	Benign	0.14	T;T;T;T
Sift4G	Benign	0.13	T;T;T;T
Polyphen		0.024	B;B;B;B
Vest4		0.20
MutPred		0.19		Loss of phosphorylation at S399 (P = 0.0125);Loss of phosphorylation at S399 (P = 0.0125);Loss of phosphorylation at S399 (P = 0.0125);Loss of phosphorylation at S399 (P = 0.0125);
MVP		0.77
MPC		0.23
ClinPred		0.063	T
GERP RS		0.70
Varity_R		0.092
gMVP		0.20

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: rs2839110; hg19: chr21-47538960;