rs78224483

Variant names:

• chr21-46001956-C-T
• rs78224483
• NM_001848.3:c.1957-5C>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_001848.3(COL6A1):​c.1957-5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0196 in 1,611,704 control chromosomes in the GnomAD database, including 389 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (40 hom., cov: 34)
  • Exomes 𝑓: 0.020 (349 hom.)
• Consequence: COL6A1 NM_001848.3 splice_region, intron
• Scores: Splicing: ADA: 0.00001802
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.836
• Publications: 2 publications found

Genes affected

COL6A1 (HGNC:2211): (collagen type VI alpha 1 chain) The collagens are a superfamily of proteins that play a role in maintaining the integrity of various tissues. Collagens are extracellular matrix proteins and have a triple-helical domain as their common structural element. Collagen VI is a major structural component of microfibrils. The basic structural unit of collagen VI is a heterotrimer of the alpha1(VI), alpha2(VI), and alpha3(VI) chains. The alpha2(VI) and alpha3(VI) chains are encoded by the COL6A2 and COL6A3 genes, respectively. The protein encoded by this gene is the alpha 1 subunit of type VI collagen (alpha1(VI) chain). Mutations in the genes that code for the collagen VI subunits result in the autosomal dominant disorder, Bethlem myopathy. [provided by RefSeq, Jul 2008]

COL6A1 Gene-Disease associations (from GenCC):

• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• collagen 6-related myopathy

  Inheritance: SD, AR, AD Classification: DEFINITIVE Submitted by: ClinGen
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AR, AD 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 21-46001956-C-T is Benign according to our data. Variant chr21-46001956-C-T is described in ClinVar as Benign. ClinVar VariationId is 93843.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 = 0.0172 (2615/152260) while in subpopulation NFE AF = 0.0264 (1796/67992). AF 95% confidence interval is 0.0254. There are 40 homozygotes in GnomAd4. There are 1266 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 40 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001848.3. 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
	COL6A1	NM_001848.3	MANE Select	c.1957-5C>T		splice_region intron	N/A	NP_001839.2	P12109

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.1957-5C>T		splice_region intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000498614.5	TSL:1	n.191-5C>T		splice_region intron	N/A
	COL6A1	ENST00000866134.1		c.565-571C>T		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.0172 AC: 2615 AN: 152142 Hom.: 40 Cov.: 34

Gnomad AFR AF: 0.00389

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.0254

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00248

Gnomad FIN AF: 0.0309

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0264

Gnomad OTH AF: 0.0148

GnomAD2 exomes AF: 0.0171 AC: 4123 AN: 241412 AF XY: 0.0172

Gnomad AFR exome AF: 0.00340

Gnomad AMR exome AF: 0.00654

Gnomad ASJ exome AF: 0.0318

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0294

Gnomad NFE exome AF: 0.0258

Gnomad OTH exome AF: 0.0172

GnomAD4 exome AF: 0.0199 AC: 28998 AN: 1459444 Hom.: 349 Cov.: 35 AF XY: 0.0198 AC XY: 14367 AN XY: 726016

African (AFR) AF: 0.00281 AC: 94 AN: 33464

American (AMR) AF: 0.00717 AC: 320 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.0293 AC: 764 AN: 26060

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.00192 AC: 165 AN: 86018

European-Finnish (FIN) AF: 0.0290 AC: 1508 AN: 51946

Middle Eastern (MID) AF: 0.00971 AC: 56 AN: 5766

European-Non Finnish (NFE) AF: 0.0226 AC: 25135 AN: 1111560

Other (OTH) AF: 0.0158 AC: 956 AN: 60318

GnomAD4 genome AF: 0.0172 AC: 2615 AN: 152260 Hom.: 40 Cov.: 34 AF XY: 0.0170 AC XY: 1266 AN XY: 74444

African (AFR) AF: 0.00387 AC: 161 AN: 41550

American (AMR) AF: 0.0127 AC: 195 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0254 AC: 88 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4826

European-Finnish (FIN) AF: 0.0309 AC: 328 AN: 10620

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

European-Non Finnish (NFE) AF: 0.0264 AC: 1796 AN: 67992

Other (OTH) AF: 0.0147 AC: 31 AN: 2110

Alfa AF: 0.0234 Hom.: 89

Bravo AF: 0.0143

Asia WGS AF: 0.00231 AC: 8 AN: 3478

EpiCase AF: 0.0233

EpiControl AF: 0.0227

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	2	not provided (2)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	0.046
DANN	Benign	0.55
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000018
dbscSNV1_RF	Benign	0.0080
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: rs78224483; hg19: chr21-47421870;