21-46111342-G-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001849.4(COL6A2):c.-27-108G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 650,608 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.017 (43 hom., cov: 31)
  • Exomes 𝑓: 0.020 (151 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.684

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]

LOC124905043 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-46111342-G-C is Benign according to our data. Variant chr21-46111342-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 677612.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0167 (2538/152344) while in subpopulation NFE AF= 0.0294 (1998/68024). AF 95% confidence interval is 0.0283. There are 43 homozygotes in gnomad4. There are 1112 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 43 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.-27-108G>C		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.-27-108G>C		intron_variant		ENST00000397763.6
LOC124905043	XR_007067910.1	n.690C>G		non_coding_transcript_exon_variant	1/2
COL6A2	NM_058175.3	c.-27-108G>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.-27-108G>C		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.-27-108G>C		intron_variant		5	NM_058174.3
COL6A2	ENST00000436769.5	c.-27-108G>C		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0167 AC: 2538 AN: 152226 Hom.: 43 Cov.: 31

Gnomad AFR AF: 0.00588

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00844

Gnomad ASJ AF: 0.0112

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00538

Gnomad FIN AF: 0.00640

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0294

Gnomad OTH AF: 0.0148

GnomAD4 exome AF: 0.0204 AC: 10147 AN: 498264 Hom.: 151 AF XY: 0.0199 AC XY: 5230 AN XY: 262626

Gnomad4 AFR exome AF: 0.00456

Gnomad4 AMR exome AF: 0.00544

Gnomad4 ASJ exome AF: 0.0142

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00709

Gnomad4 FIN exome AF: 0.00937

Gnomad4 NFE exome AF: 0.0291

Gnomad4 OTH exome AF: 0.0182

GnomAD4 genome AF: 0.0167 AC: 2538 AN: 152344 Hom.: 43 Cov.: 31 AF XY: 0.0149 AC XY: 1112 AN XY: 74500

Gnomad4 AFR AF: 0.00587

Gnomad4 AMR AF: 0.00849

Gnomad4 ASJ AF: 0.0112

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00497

Gnomad4 FIN AF: 0.00640

Gnomad4 NFE AF: 0.0294

Gnomad4 OTH AF: 0.0147

Alfa AF: 0.0235 Hom.: 5

Bravo AF: 0.0159

Asia WGS AF: 0.00346 AC: 12 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely 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	-0.86
Cadd	Benign	1.7
Dann	Benign	0.79

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs77745490; hg19: chr21-47531256;