chr21-46111301-C-T

Variant names:

• chr21-46111301-C-T
• rs13050828
• NM_001849.4:c.-27-149C>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.-27-149C>T 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 587,398 control chromosomes in the GnomAD database, including 73,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.44 (16835 hom., cov: 33)
  • Exomes 𝑓: 0.50 (56774 hom.)
• Consequence: COL6A2 NM_001849.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.290
• 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, SD, 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: AR, AD Classification: STRONG Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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=-0.81).
• BP6: Variant 21-46111301-C-T is Benign according to our data. Variant chr21-46111301-C-T is described in ClinVar as Benign. ClinVar VariationId is 679204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.566 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	NM_001849.4	MANE Select	c.-27-149C>T		intron	N/A	NP_001840.3
	COL6A2	NM_058174.3	MANE Plus Clinical	c.-27-149C>T		intron	N/A	NP_478054.2	P12110-2
	COL6A2	NM_058175.3		c.-27-149C>T		intron	N/A	NP_478055.2	P12110-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A2	ENST00000300527.9	TSL:1 MANE Select	c.-27-149C>T		intron	N/A	ENSP00000300527.4	P12110-1
	COL6A2	ENST00000397763.6	TSL:5 MANE Plus Clinical	c.-27-149C>T		intron	N/A	ENSP00000380870.1	P12110-2
	COL6A2	ENST00000968884.1		c.-176C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 27	ENSP00000638943.1

Frequencies

GnomAD3 genomes AF: 0.441 AC: 67094 AN: 152054 Hom.: 16818 Cov.: 33

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.581

Gnomad AMR AF: 0.575

Gnomad ASJ AF: 0.542

Gnomad EAS AF: 0.428

Gnomad SAS AF: 0.362

Gnomad FIN AF: 0.644

Gnomad MID AF: 0.449

Gnomad NFE AF: 0.532

Gnomad OTH AF: 0.457

GnomAD4 exome AF: 0.501 AC: 217999 AN: 435226 Hom.: 56774 AF XY: 0.494 AC XY: 112774 AN XY: 228428

African (AFR) AF: 0.190 AC: 2328 AN: 12260

American (AMR) AF: 0.620 AC: 12568 AN: 20260

Ashkenazi Jewish (ASJ) AF: 0.538 AC: 7232 AN: 13436

East Asian (EAS) AF: 0.413 AC: 12384 AN: 29970

South Asian (SAS) AF: 0.364 AC: 16781 AN: 46112

European-Finnish (FIN) AF: 0.637 AC: 18326 AN: 28766

Middle Eastern (MID) AF: 0.455 AC: 864 AN: 1900

European-Non Finnish (NFE) AF: 0.525 AC: 135060 AN: 257476

Other (OTH) AF: 0.497 AC: 12456 AN: 25046

GnomAD4 genome AF: 0.441 AC: 67125 AN: 152172 Hom.: 16835 Cov.: 33 AF XY: 0.448 AC XY: 33306 AN XY: 74374

African (AFR) AF: 0.190 AC: 7913 AN: 41540

American (AMR) AF: 0.576 AC: 8803 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.542 AC: 1878 AN: 3468

East Asian (EAS) AF: 0.428 AC: 2210 AN: 5162

South Asian (SAS) AF: 0.363 AC: 1750 AN: 4824

European-Finnish (FIN) AF: 0.644 AC: 6813 AN: 10586

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36140 AN: 67982

Other (OTH) AF: 0.453 AC: 957 AN: 2114

Alfa AF: 0.497 Hom.: 3034

Bravo AF: 0.426

Asia WGS AF: 0.400 AC: 1391 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	4.4
DANN	Benign	0.57
PhyloP100		-0.29
PromoterAI		-0.013	Neutral
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: rs13050828; hg19: chr21-47531215; COSMIC: COSV56001657; COSMIC: COSV56001657;