rs78764604

Positions:

• chr21-46125762-G-C
• chr21-46125762-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.1970-23G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0803 in 1,608,478 control chromosomes in the GnomAD database, including 6,208 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.056 (354 hom., cov: 33)
  • Exomes 𝑓: 0.083 (5854 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -3.20

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-46125762-G-C is Benign according to our data. Variant chr21-46125762-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 93926.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.09 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1970-23G>C		intron_variant		ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1970-23G>C		intron_variant		ENST00000397763.6	NP_478054.2
COL6A2	NM_058175.3	c.1970-23G>C		intron_variant			NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1970-23G>C		intron_variant		1	NM_001849.4	ENSP00000300527	P1
COL6A2	ENST00000397763.6	c.1970-23G>C		intron_variant		5	NM_058174.3	ENSP00000380870
COL6A2	ENST00000409416.6	c.1970-23G>C		intron_variant		5		ENSP00000387115
COL6A2	ENST00000413758.1	c.641-23G>C		intron_variant		3		ENSP00000395751

Frequencies

GnomAD3 genomes AF: 0.0559 AC: 8512 AN: 152170 Hom.: 354 Cov.: 33

Gnomad AFR AF: 0.0179

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0471

Gnomad ASJ AF: 0.0723

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0339

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0919

Gnomad OTH AF: 0.0580

GnomAD3 exomes AF: 0.0556 AC: 13607 AN: 244564 Hom.: 497 AF XY: 0.0567 AC XY: 7572 AN XY: 133566

Gnomad AFR exome AF: 0.0160

Gnomad AMR exome AF: 0.0309

Gnomad ASJ exome AF: 0.0757

Gnomad EAS exome AF: 0.00115

Gnomad SAS exome AF: 0.0150

Gnomad FIN exome AF: 0.0356

Gnomad NFE exome AF: 0.0907

Gnomad OTH exome AF: 0.0695

GnomAD4 exome AF: 0.0828 AC: 120611 AN: 1456190 Hom.: 5854 Cov.: 37 AF XY: 0.0808 AC XY: 58451 AN XY: 723586

Gnomad4 AFR exome AF: 0.0135

Gnomad4 AMR exome AF: 0.0329

Gnomad4 ASJ exome AF: 0.0774

Gnomad4 EAS exome AF: 0.00106

Gnomad4 SAS exome AF: 0.0151

Gnomad4 FIN exome AF: 0.0387

Gnomad4 NFE exome AF: 0.0979

Gnomad4 OTH exome AF: 0.0762

GnomAD4 genome AF: 0.0559 AC: 8512 AN: 152288 Hom.: 354 Cov.: 33 AF XY: 0.0527 AC XY: 3922 AN XY: 74468

Gnomad4 AFR AF: 0.0179

Gnomad4 AMR AF: 0.0471

Gnomad4 ASJ AF: 0.0723

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0116

Gnomad4 FIN AF: 0.0339

Gnomad4 NFE AF: 0.0919

Gnomad4 OTH AF: 0.0573

Alfa AF: 0.0412 Hom.: 44

Bravo AF: 0.0558

Asia WGS AF: 0.0150 AC: 53 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 16, 2012	- -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 16, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.022
DANN	Benign	0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs78764604; hg19: chr21-47545676;