21-46001401-C-T

Variant names:

• chr21-46001401-C-T
• rs11701124
• NM_001848.3:c.1956+15C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001848.3(COL6A1):​c.1956+15C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,607,804 control chromosomes in the GnomAD database, including 193,108 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18779 hom., cov: 35)
  • Exomes 𝑓: 0.49 (174329 hom.)
• Consequence: COL6A1 NM_001848.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -4.33
• Publications: 13 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, AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 21-46001401-C-T is Benign according to our data. Variant chr21-46001401-C-T is described in ClinVar as Benign. ClinVar VariationId is 93841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.693 is higher than 0.05.

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.1956+15C>T		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.1956+15C>T		intron	N/A	ENSP00000355180.3	P12109
	COL6A1	ENST00000498614.5	TSL:1	n.190+15C>T		intron	N/A
	COL6A1	ENST00000866134.1		c.565-1126C>T		intron	N/A	ENSP00000536193.1

Frequencies

GnomAD3 genomes AF: 0.494 AC: 75025 AN: 151994 Hom.: 18764 Cov.: 35

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.556

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.541

Gnomad EAS AF: 0.712

Gnomad SAS AF: 0.554

Gnomad FIN AF: 0.505

Gnomad MID AF: 0.528

Gnomad NFE AF: 0.475

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.527 AC: 129065 AN: 245106 AF XY: 0.524

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.596

Gnomad ASJ exome AF: 0.554

Gnomad EAS exome AF: 0.713

Gnomad FIN exome AF: 0.515

Gnomad NFE exome AF: 0.477

Gnomad OTH exome AF: 0.532

GnomAD4 exome AF: 0.486 AC: 707927 AN: 1455692 Hom.: 174329 Cov.: 52 AF XY: 0.488 AC XY: 353704 AN XY: 724350

African (AFR) AF: 0.467 AC: 15619 AN: 33458

American (AMR) AF: 0.592 AC: 26467 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.545 AC: 14234 AN: 26112

East Asian (EAS) AF: 0.691 AC: 27406 AN: 39678

South Asian (SAS) AF: 0.544 AC: 46901 AN: 86248

European-Finnish (FIN) AF: 0.515 AC: 24717 AN: 47952

Middle Eastern (MID) AF: 0.526 AC: 3032 AN: 5766

European-Non Finnish (NFE) AF: 0.467 AC: 519123 AN: 1111464

Other (OTH) AF: 0.505 AC: 30428 AN: 60308

GnomAD4 genome AF: 0.494 AC: 75087 AN: 152112 Hom.: 18779 Cov.: 35 AF XY: 0.496 AC XY: 36869 AN XY: 74318

African (AFR) AF: 0.469 AC: 19448 AN: 41502

American (AMR) AF: 0.527 AC: 8058 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.541 AC: 1880 AN: 3472

East Asian (EAS) AF: 0.712 AC: 3664 AN: 5146

South Asian (SAS) AF: 0.554 AC: 2670 AN: 4816

European-Finnish (FIN) AF: 0.505 AC: 5351 AN: 10586

Middle Eastern (MID) AF: 0.514 AC: 151 AN: 294

European-Non Finnish (NFE) AF: 0.475 AC: 32295 AN: 67972

Other (OTH) AF: 0.503 AC: 1063 AN: 2114

Alfa AF: 0.497 Hom.: 3485

Bravo AF: 0.494

Asia WGS AF: 0.625 AC: 2173 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	1	Bethlem myopathy 1A (1)
-	-	1	Collagen 6-related myopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.41
DANN	Benign	0.84
PhyloP100		-4.3
PromoterAI		0.022	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: rs11701124; hg19: chr21-47421315; COSMIC: COSV62612855; COSMIC: COSV62612855;