NM_001849.4:c.1116+39C>T

Variant names:

• chr21-46117975-C-T
• rs180796593
• NM_001849.4:c.1116+39C>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_001849.4(COL6A2):​c.1116+39C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00141 in 1,587,438 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0030 (8 hom., cov: 33)
  • Exomes 𝑓: 0.0012 (37 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.08
• 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=-0.85).
• BP6: Variant 21-46117975-C-T is Benign according to our data. Variant chr21-46117975-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 258313.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 = 0.00304 (463/152204) while in subpopulation AMR AF = 0.0261 (399/15300). AF 95% confidence interval is 0.024. There are 8 homozygotes in GnomAd4. There are 256 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001849.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.1116+39C>T		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.1116+39C>T		intron	N/A	NP_478054.2
	COL6A2	NM_058175.3		c.1116+39C>T		intron	N/A	NP_478055.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.1116+39C>T		intron	N/A	ENSP00000300527.4
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.1116+39C>T		intron	N/A	ENSP00000380870.1
	COL6A2	ENST00000857098.1		c.1116+39C>T		intron	N/A	ENSP00000527157.1

Frequencies

GnomAD3 genomes AF: 0.00304 AC: 462 AN: 152086 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.000869

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0260

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00232

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00569 AC: 1298 AN: 228260 AF XY: 0.00420

Gnomad AFR exome AF: 0.000828

Gnomad AMR exome AF: 0.0382

Gnomad ASJ exome AF: 0.000111

Gnomad EAS exome AF: 0.00145

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000779

Gnomad OTH exome AF: 0.00345

GnomAD4 exome AF: 0.00123 AC: 1769 AN: 1435234 Hom.: 37 Cov.: 28 AF XY: 0.00106 AC XY: 752 AN XY: 711148

African (AFR) AF: 0.000696 AC: 23 AN: 33030

American (AMR) AF: 0.0361 AC: 1545 AN: 42796

Ashkenazi Jewish (ASJ) AF: 0.0000395 AC: 1 AN: 25314

East Asian (EAS) AF: 0.00187 AC: 73 AN: 39100

South Asian (SAS) AF: 0.0000837 AC: 7 AN: 83664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51446

Middle Eastern (MID) AF: 0.000352 AC: 2 AN: 5676

European-Non Finnish (NFE) AF: 0.0000429 AC: 47 AN: 1094980

Other (OTH) AF: 0.00120 AC: 71 AN: 59228

GnomAD4 genome AF: 0.00304 AC: 463 AN: 152204 Hom.: 8 Cov.: 33 AF XY: 0.00344 AC XY: 256 AN XY: 74406

African (AFR) AF: 0.000867 AC: 36 AN: 41542

American (AMR) AF: 0.0261 AC: 399 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00233 AC: 12 AN: 5150

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67972

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00151 Hom.: 1

Bravo AF: 0.00541

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.036
DANN	Benign	0.67
PhyloP100		-1.1
Mutation Taster		=100/0	polymorphism

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: rs180796593; hg19: chr21-47537889;