21-46124627-C-G

Variant names:

• chr21-46124627-C-G
• rs3746995
• NM_001849.4:c.1672-24C>G

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.1672-24C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.485 in 1,610,766 control chromosomes in the GnomAD database, including 195,012 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.45 (16417 hom., cov: 32)
  • Exomes 𝑓: 0.49 (178595 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.789
• Publications: 9 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: This position, referring to a specific DNA site, is a probable branch point but rather VUS (scored 4 / 10). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 21-46124627-C-G is Benign according to our data. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-46124627-C-G is described in CliVar as Benign. Clinvar id is 93916.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.568 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.1672-24C>G		intron_variant	Intron 21 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058174.3	c.1672-24C>G		intron_variant	Intron 21 of 27		NP_478054.2
COL6A2	NM_058175.3	c.1672-24C>G		intron_variant	Intron 21 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.1672-24C>G		intron_variant	Intron 21 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.1672-24C>G		intron_variant	Intron 21 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.1672-24C>G		intron_variant	Intron 20 of 26	5		ENSP00000387115.1
COL6A2	ENST00000413758.1	c.295-24C>G		intron_variant	Intron 6 of 10	3		ENSP00000395751.1

Frequencies

GnomAD3 genomes AF: 0.446 AC: 67700 AN: 151794 Hom.: 16402 Cov.: 32

Gnomad AFR AF: 0.251

Gnomad AMI AF: 0.582

Gnomad AMR AF: 0.577

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.452

Gnomad SAS AF: 0.333

Gnomad FIN AF: 0.618

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.510

Gnomad OTH AF: 0.460

GnomAD2 exomes AF: 0.493 AC: 122940 AN: 249358 AF XY: 0.483

Gnomad AFR exome AF: 0.242

Gnomad AMR exome AF: 0.654

Gnomad ASJ exome AF: 0.516

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.624

Gnomad NFE exome AF: 0.504

Gnomad OTH exome AF: 0.517

GnomAD4 exome AF: 0.489 AC: 713094 AN: 1458852 Hom.: 178595 Cov.: 36 AF XY: 0.484 AC XY: 351331 AN XY: 725828

African (AFR) AF: 0.229 AC: 7657 AN: 33446

American (AMR) AF: 0.645 AC: 28836 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.517 AC: 13492 AN: 26110

East Asian (EAS) AF: 0.436 AC: 17299 AN: 39684

South Asian (SAS) AF: 0.331 AC: 28534 AN: 86226

European-Finnish (FIN) AF: 0.615 AC: 32212 AN: 52358

Middle Eastern (MID) AF: 0.431 AC: 2471 AN: 5730

European-Non Finnish (NFE) AF: 0.499 AC: 553764 AN: 1110298

Other (OTH) AF: 0.478 AC: 28829 AN: 60300

GnomAD4 genome AF: 0.446 AC: 67732 AN: 151914 Hom.: 16417 Cov.: 32 AF XY: 0.451 AC XY: 33505 AN XY: 74234

African (AFR) AF: 0.250 AC: 10380 AN: 41446

American (AMR) AF: 0.578 AC: 8832 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1804 AN: 3472

East Asian (EAS) AF: 0.453 AC: 2322 AN: 5130

South Asian (SAS) AF: 0.333 AC: 1605 AN: 4814

European-Finnish (FIN) AF: 0.618 AC: 6546 AN: 10594

Middle Eastern (MID) AF: 0.429 AC: 126 AN: 294

European-Non Finnish (NFE) AF: 0.510 AC: 34628 AN: 67864

Other (OTH) AF: 0.455 AC: 959 AN: 2106

Alfa AF: 0.414 Hom.: 2163

Bravo AF: 0.437

Asia WGS AF: 0.403 AC: 1401 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Nov 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

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 14, 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. -

Myosclerosis Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Bethlem myopathy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ullrich congenital muscular dystrophy 1A Benign:1

Jul 30, 2021

Genome-Nilou Lab

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	-0.73
CADD	Benign	12
DANN	Benign	0.78
PhyloP100		0.79
BranchPoint Hunter		4.0
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: rs3746995; hg19: chr21-47544541; COSMIC: COSV56007540;