21-46111361-G-A

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.-27-89G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00517 in 713,700 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.015 (53 hom., cov: 31)
  • Exomes 𝑓: 0.0024 (24 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -3.77

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=-0.91).
• BP6: Variant 21-46111361-G-A is Benign according to our data. Variant chr21-46111361-G-A is described in ClinVar as [Benign]. Clinvar id is 679820.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0152 (2321/152314) while in subpopulation AFR AF= 0.0499 (2074/41572). AF 95% confidence interval is 0.0481. There are 53 homozygotes in gnomad4. There are 1113 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 53 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL6A2	NM_001849.4	c.-27-89G>A		intron_variant		ENST00000300527.9
COL6A2	NM_058174.3	c.-27-89G>A		intron_variant		ENST00000397763.6
LOC124905043	XR_007067910.1	n.671C>T		non_coding_transcript_exon_variant	1/2
COL6A2	NM_058175.3	c.-27-89G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL6A2	ENST00000300527.9	c.-27-89G>A		intron_variant		1	NM_001849.4	P1
COL6A2	ENST00000397763.6	c.-27-89G>A		intron_variant		5	NM_058174.3
COL6A2	ENST00000436769.5	c.-27-89G>A		intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0152 AC: 2318 AN: 152196 Hom.: 53 Cov.: 31

Gnomad AFR AF: 0.0499

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00955

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00868

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000412

Gnomad OTH AF: 0.0124

GnomAD4 exome AF: 0.00244 AC: 1369 AN: 561386 Hom.: 24 AF XY: 0.00208 AC XY: 613 AN XY: 295350

Gnomad4 AFR exome AF: 0.0469

Gnomad4 AMR exome AF: 0.00426

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00536

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.0000254

Gnomad4 NFE exome AF: 0.000387

Gnomad4 OTH exome AF: 0.00567

GnomAD4 genome AF: 0.0152 AC: 2321 AN: 152314 Hom.: 53 Cov.: 31 AF XY: 0.0149 AC XY: 1113 AN XY: 74472

Gnomad4 AFR AF: 0.0499

Gnomad4 AMR AF: 0.00954

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00850

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000412

Gnomad4 OTH AF: 0.0123

Alfa AF: 0.0129 Hom.: 2

Bravo AF: 0.0180

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

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	-0.91
Cadd	Benign	0.44
Dann	Benign	0.62

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: rs115342490; hg19: chr21-47531275; COSMIC: COSV100153131; COSMIC: COSV100153131;