21-46112622-C-T

Variant names:

• chr21-46112622-C-T
• rs2070957
• NM_001849.4:c.714+45C>T

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.714+45C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0567 in 1,601,862 control chromosomes in the GnomAD database, including 6,158 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (1193 hom., cov: 32)
  • Exomes 𝑓: 0.052 (4965 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.278
• Publications: 4 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=-0.89).
• BP6: Variant 21-46112622-C-T is Benign according to our data. Variant chr21-46112622-C-T is described in ClinVar as [Benign]. Clinvar id is 93958.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.282 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.714+45C>T		intron_variant	Intron 3 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.714+45C>T		intron_variant	Intron 3 of 27		NP_478054.2
COL6A2	NM_058175.3	c.714+45C>T		intron_variant	Intron 3 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.714+45C>T		intron_variant	Intron 3 of 27	1	NM_001849.4	ENSP00000300527.4

Frequencies

GnomAD3 genomes AF: 0.0967 AC: 14698 AN: 152034 Hom.: 1191 Cov.: 32

Gnomad AFR AF: 0.199

Gnomad AMI AF: 0.0716

Gnomad AMR AF: 0.0963

Gnomad ASJ AF: 0.0369

Gnomad EAS AF: 0.294

Gnomad SAS AF: 0.0876

Gnomad FIN AF: 0.0183

Gnomad MID AF: 0.0759

Gnomad NFE AF: 0.0358

Gnomad OTH AF: 0.108

GnomAD2 exomes AF: 0.0804 AC: 19368 AN: 240852 AF XY: 0.0754

Gnomad AFR exome AF: 0.204

Gnomad AMR exome AF: 0.101

Gnomad ASJ exome AF: 0.0327

Gnomad EAS exome AF: 0.289

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0599

GnomAD4 exome AF: 0.0524 AC: 76026 AN: 1449708 Hom.: 4965 Cov.: 33 AF XY: 0.0527 AC XY: 38028 AN XY: 721420

African (AFR) AF: 0.202 AC: 6726 AN: 33320

American (AMR) AF: 0.101 AC: 4528 AN: 44614

Ashkenazi Jewish (ASJ) AF: 0.0337 AC: 877 AN: 26034

East Asian (EAS) AF: 0.366 AC: 14492 AN: 39586

South Asian (SAS) AF: 0.0783 AC: 6737 AN: 86014

European-Finnish (FIN) AF: 0.0191 AC: 966 AN: 50652

Middle Eastern (MID) AF: 0.0765 AC: 439 AN: 5736

European-Non Finnish (NFE) AF: 0.0338 AC: 37339 AN: 1103746

Other (OTH) AF: 0.0654 AC: 3922 AN: 60006

GnomAD4 genome AF: 0.0967 AC: 14720 AN: 152154 Hom.: 1193 Cov.: 32 AF XY: 0.0972 AC XY: 7234 AN XY: 74416

African (AFR) AF: 0.199 AC: 8248 AN: 41530

American (AMR) AF: 0.0960 AC: 1467 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0369 AC: 128 AN: 3468

East Asian (EAS) AF: 0.294 AC: 1507 AN: 5124

South Asian (SAS) AF: 0.0879 AC: 424 AN: 4826

European-Finnish (FIN) AF: 0.0183 AC: 194 AN: 10612

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0358 AC: 2433 AN: 68000

Other (OTH) AF: 0.109 AC: 230 AN: 2110

Alfa AF: 0.0238 Hom.: 15

Bravo AF: 0.109

Asia WGS AF: 0.163 AC: 567 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 19, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	-0.89
CADD	Benign	2.8
DANN	Benign	0.81
PhyloP100		-0.28
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: rs2070957; hg19: chr21-47532536; COSMIC: COSV56001721; COSMIC: COSV56001721;