chr21-46098272-T-C

Variant names:

• chr21-46098272-T-C
• rs2277817
• NM_001849.4:c.-28+99T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001849.4(COL6A2):​c.-28+99T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.846 in 152,254 control chromosomes in the GnomAD database, including 54,651 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (54468 hom., cov: 34)
  • Exomes 𝑓: 0.87 (183 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.39
• Publications: 0 publications found

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]

COL6A2 Gene-Disease associations (from GenCC):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1B

  Inheritance: AR, AD Classification: DEFINITIVE Submitted by: G2P
• Bethlem myopathy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Genomics England PanelApp
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Bethlem myopathy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ullrich congenital muscular dystrophy

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• myosclerosis

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 21-46098272-T-C is Benign according to our data. Variant chr21-46098272-T-C is described in ClinVar as [Benign]. Clinvar id is 1231952.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.873 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.-28+99T>C		intron_variant	Intron 1 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.-28+99T>C		intron_variant	Intron 1 of 27		NP_478054.2
COL6A2	NM_058175.3	c.-28+99T>C		intron_variant	Intron 1 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.-28+99T>C		intron_variant	Intron 1 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.-28+99T>C		intron_variant	Intron 1 of 27	5		ENSP00000380870.1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128256 AN: 151668 Hom.: 54438 Cov.: 34

Gnomad AFR AF: 0.806

Gnomad AMI AF: 0.922

Gnomad AMR AF: 0.847

Gnomad ASJ AF: 0.885

Gnomad EAS AF: 0.647

Gnomad SAS AF: 0.895

Gnomad FIN AF: 0.939

Gnomad MID AF: 0.908

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.831

GnomAD4 exome AF: 0.872 AC: 415 AN: 476 Hom.: 183 AF XY: 0.880 AC XY: 257 AN XY: 292

African (AFR) AF: 1.00 AC: 4 AN: 4

American (AMR) AF: 1.00 AC: 2 AN: 2

Ashkenazi Jewish (ASJ) AF: 0.750 AC: 3 AN: 4

East Asian (EAS) AF: 0.357 AC: 5 AN: 14

South Asian (SAS) AF: 0.886 AC: 140 AN: 158

European-Finnish (FIN) AF: 1.00 AC: 4 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.888 AC: 245 AN: 276

Other (OTH) AF: 0.857 AC: 12 AN: 14

GnomAD4 genome AF: 0.846 AC: 128336 AN: 151778 Hom.: 54468 Cov.: 34 AF XY: 0.848 AC XY: 62944 AN XY: 74190

African (AFR) AF: 0.806 AC: 33389 AN: 41450

American (AMR) AF: 0.847 AC: 12935 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.885 AC: 3072 AN: 3470

East Asian (EAS) AF: 0.646 AC: 3260 AN: 5044

South Asian (SAS) AF: 0.896 AC: 4320 AN: 4824

European-Finnish (FIN) AF: 0.939 AC: 9907 AN: 10554

Middle Eastern (MID) AF: 0.901 AC: 263 AN: 292

European-Non Finnish (NFE) AF: 0.864 AC: 58600 AN: 67856

Other (OTH) AF: 0.830 AC: 1749 AN: 2106

Alfa AF: 0.844 Hom.: 2718

Bravo AF: 0.833

Asia WGS AF: 0.796 AC: 2649 AN: 3326

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 03, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	6.5
DANN	Benign	0.39
PhyloP100		-1.4
PromoterAI		0.081	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2277817; hg19: chr21-47518186;