rs76978157

Variant names:

• chr21-46129496-C-T
• rs76978157
• NM_058174.3:c.*5C>T

Variant summary

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

The NM_058174.3(COL6A2):​c.*5C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0144 in 1,561,784 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (17 hom., cov: 33)
  • Exomes 𝑓: 0.015 (216 hom.)
• Consequence: COL6A2 NM_058174.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -4.68
• Publications: 1 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=-0.88).
• BP6: Variant 21-46129496-C-T is Benign according to our data. Variant chr21-46129496-C-T is described in ClinVar as Benign. ClinVar VariationId is 262300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0125 (1900/152206) while in subpopulation AMR AF = 0.0203 (310/15286). AF 95% confidence interval is 0.0184. There are 17 homozygotes in GnomAd4. There are 921 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 17 AR,AD gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL6A2	NM_058174.3	c.*5C>T		3_prime_UTR_variant	Exon 28 of 28	ENST00000397763.6	NP_478054.2
COL6A2	NM_001849.4	c.2462-2458C>T		intron_variant	Intron 27 of 27	ENST00000300527.9	NP_001840.3
COL6A2	NM_058175.3	c.*568C>T		3_prime_UTR_variant	Exon 28 of 28		NP_478055.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL6A2	ENST00000397763.6	c.*5C>T		3_prime_UTR_variant	Exon 28 of 28	5	NM_058174.3	ENSP00000380870.1
COL6A2	ENST00000300527.9	c.2462-2458C>T		intron_variant	Intron 27 of 27	1	NM_001849.4	ENSP00000300527.4
COL6A2	ENST00000409416.6	c.*568C>T		3_prime_UTR_variant	Exon 27 of 27	5		ENSP00000387115.1

Frequencies

GnomAD3 genomes AF: 0.0125 AC: 1902 AN: 152088 Hom.: 17 Cov.: 33

Gnomad AFR AF: 0.00365

Gnomad AMI AF: 0.0691

Gnomad AMR AF: 0.0203

Gnomad ASJ AF: 0.0147

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00498

Gnomad FIN AF: 0.00913

Gnomad MID AF: 0.0443

Gnomad NFE AF: 0.0169

Gnomad OTH AF: 0.0206

GnomAD2 exomes AF: 0.0130 AC: 2550 AN: 196730 AF XY: 0.0135

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.0137

Gnomad EAS exome AF: 0.000848

Gnomad FIN exome AF: 0.00860

Gnomad NFE exome AF: 0.0195

Gnomad OTH exome AF: 0.0146

GnomAD4 exome AF: 0.0146 AC: 20565 AN: 1409578 Hom.: 216 Cov.: 31 AF XY: 0.0144 AC XY: 10041 AN XY: 695038

African (AFR) AF: 0.00285 AC: 93 AN: 32584

American (AMR) AF: 0.0127 AC: 520 AN: 40980

Ashkenazi Jewish (ASJ) AF: 0.0143 AC: 335 AN: 23350

East Asian (EAS) AF: 0.000231 AC: 9 AN: 38948

South Asian (SAS) AF: 0.00484 AC: 387 AN: 80010

European-Finnish (FIN) AF: 0.00814 AC: 361 AN: 44336

Middle Eastern (MID) AF: 0.0299 AC: 163 AN: 5448

European-Non Finnish (NFE) AF: 0.0165 AC: 17910 AN: 1085806

Other (OTH) AF: 0.0135 AC: 787 AN: 58116

GnomAD4 genome AF: 0.0125 AC: 1900 AN: 152206 Hom.: 17 Cov.: 33 AF XY: 0.0124 AC XY: 921 AN XY: 74446

African (AFR) AF: 0.00364 AC: 151 AN: 41534

American (AMR) AF: 0.0203 AC: 310 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0147 AC: 51 AN: 3470

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00477 AC: 23 AN: 4820

European-Finnish (FIN) AF: 0.00913 AC: 97 AN: 10622

Middle Eastern (MID) AF: 0.0442 AC: 13 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1148 AN: 67992

Other (OTH) AF: 0.0204 AC: 43 AN: 2110

Alfa AF: 0.0142 Hom.: 3

Bravo AF: 0.0135

Asia WGS AF: 0.00520 AC: 18 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: 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	-0.88
CADD	Benign	0.0060
DANN	Benign	0.62
PhyloP100		-4.7
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: rs76978157; hg19: chr21-47549410;