chr21-46111945-G-A

Variant names:

• chr21-46111945-G-A
• rs117154313
• NM_001849.4:c.116-34G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001849.4(COL6A2):​c.116-34G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0239 in 1,600,712 control chromosomes in the GnomAD database, including 615 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.020 (50 hom., cov: 32)
  • Exomes 𝑓: 0.024 (565 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.39
• Publications: 3 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

LOC124905043 (HGNC:):

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 21-46111945-G-A is Benign according to our data. Variant chr21-46111945-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0203 (3084/152262) while in subpopulation NFE AF = 0.0298 (2029/68006). AF 95% confidence interval is 0.0288. There are 50 homozygotes in GnomAd4. There are 1504 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 50 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_001849.4	c.116-34G>A		intron_variant	Intron 2 of 27	ENST00000300527.9	NP_001840.3
LOC124905043	XR_007067910.1	n.87C>T		non_coding_transcript_exon_variant	Exon 1 of 2
COL6A2	NM_058174.3	c.116-34G>A		intron_variant	Intron 2 of 27		NP_478054.2
COL6A2	NM_058175.3	c.116-34G>A		intron_variant	Intron 2 of 27		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000300527.9	c.116-34G>A		intron_variant	Intron 2 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000397763.6	c.116-34G>A		intron_variant	Intron 2 of 27	5		ENSP00000380870.1
COL6A2	ENST00000409416.6	c.116-34G>A		intron_variant	Intron 1 of 26	5		ENSP00000387115.1
COL6A2	ENST00000436769.5	c.116-34G>A		intron_variant	Intron 2 of 2	2		ENSP00000390418.1

Frequencies

GnomAD3 genomes AF: 0.0203 AC: 3083 AN: 152144 Hom.: 50 Cov.: 32

Gnomad AFR AF: 0.00447

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0111

Gnomad ASJ AF: 0.0582

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.0380

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0298

Gnomad OTH AF: 0.0196

GnomAD2 exomes AF: 0.0215 AC: 5232 AN: 243146 AF XY: 0.0218

Gnomad AFR exome AF: 0.00403

Gnomad AMR exome AF: 0.00707

Gnomad ASJ exome AF: 0.0614

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0371

Gnomad NFE exome AF: 0.0302

Gnomad OTH exome AF: 0.0200

GnomAD4 exome AF: 0.0242 AC: 35123 AN: 1448450 Hom.: 565 Cov.: 31 AF XY: 0.0239 AC XY: 17258 AN XY: 721196

African (AFR) AF: 0.00351 AC: 117 AN: 33324

American (AMR) AF: 0.00774 AC: 346 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 1523 AN: 26082

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39664

South Asian (SAS) AF: 0.00670 AC: 577 AN: 86114

European-Finnish (FIN) AF: 0.0367 AC: 1747 AN: 47620

Middle Eastern (MID) AF: 0.0122 AC: 70 AN: 5756

European-Non Finnish (NFE) AF: 0.0266 AC: 29429 AN: 1105072

Other (OTH) AF: 0.0218 AC: 1313 AN: 60104

GnomAD4 genome AF: 0.0203 AC: 3084 AN: 152262 Hom.: 50 Cov.: 32 AF XY: 0.0202 AC XY: 1504 AN XY: 74448

African (AFR) AF: 0.00445 AC: 185 AN: 41534

American (AMR) AF: 0.0110 AC: 169 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0582 AC: 202 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4824

European-Finnish (FIN) AF: 0.0380 AC: 404 AN: 10622

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0298 AC: 2029 AN: 68006

Other (OTH) AF: 0.0194 AC: 41 AN: 2114

Alfa AF: 0.0282 Hom.: 114

Bravo AF: 0.0173

Asia WGS AF: 0.00144 AC: 5 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2012

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.0
DANN	Benign	0.86
PhyloP100		-1.4
PromoterAI		0.0056	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: 3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs117154313; hg19: chr21-47531859;