rs143338050

chr21-46122529-G-Cchr21-46122529-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001849.4(COL6A2):c.1606G>C(p.Glu536Gln) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,474 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E536K) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: COL6A2 NM_001849.4 missense, splice_region
• Scores: Splicing: ADA: 0.0009399
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.39

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.33312643).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.1606G>C	p.Glu536Gln	missense_variant, splice_region_variant	20/28	ENST00000300527.9
COL6A2	NM_058174.3	c.1606G>C	p.Glu536Gln	missense_variant, splice_region_variant	20/28	ENST00000397763.6
COL6A2	NM_058175.3	c.1606G>C	p.Glu536Gln	missense_variant, splice_region_variant	20/28

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.1606G>C	p.Glu536Gln	missense_variant, splice_region_variant	20/28	1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.1606G>C	p.Glu536Gln	missense_variant, splice_region_variant	20/28	5	NM_058174.3
COL6A2	ENST00000409416.6	c.1606G>C	p.Glu536Gln	missense_variant, splice_region_variant	19/27	5
COL6A2	ENST00000413758.1	c.229G>C	p.Glu77Gln	missense_variant, splice_region_variant	5/11	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000401 AC: 1 AN: 249096 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1460474 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 726524

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000826 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.23	T;.;.;.;T
Eigen	Benign	-0.041
Eigen_PC	Benign	0.013
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.87	D;D;.;D;D
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.33	T;T;T;T;T
MetaSVM	Uncertain	-0.14	T
MutationAssessor	Benign	-0.71	N;N;N;N;.
MutationTaster	Benign	0.90	N;N;N;N;N
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.30	N;N;N;N;N
REVEL	Benign	0.26
Sift	Benign	0.34	T;T;T;T;T
Sift4G	Benign	0.55	T;T;T;T;T
Polyphen		0.94	P;P;P;P;.
Vest4		0.35
MutPred		0.26		Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);Gain of MoRF binding (P = 0.0412);.;
MVP		0.99
MPC		0.15
ClinPred		0.21	T
GERP RS		4.3
Varity_R		0.086
gMVP		0.21

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00094
dbscSNV1_RF	Benign	0.012
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: rs143338050; hg19: chr21-47542443;