21-46002298-C-T

Variant names:

• chr21-46002298-C-T
• rs755589190
• NM_001848.3:c.2147C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4 BS1_Supporting

The NM_001848.3(COL6A1):​c.2147C>T​(p.Pro716Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000139 in 1,441,212 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P716P) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: COL6A1 NM_001848.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 0.0740
• Publications: 1 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):

• collagen 6-related myopathy

  Inheritance: AD, AR Classification: DEFINITIVE Submitted by: ClinGen
• Bethlem myopathy 1A

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P
• Ullrich congenital muscular dystrophy 1A

  Inheritance: AD, AR 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2674939).
• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.0000139 (20/1441212) while in subpopulation MID AF = 0.000874 (5/5724). AF 95% confidence interval is 0.000343. There are 0 homozygotes in GnomAdExome4. There are 12 alleles in the male GnomAdExome4 subpopulation. Median coverage is 35. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	NM_001848.3	MANE Select	c.2147C>T	p.Pro716Leu	missense	Exon 32 of 35	NP_001839.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A1	ENST00000361866.8	TSL:1 MANE Select	c.2147C>T	p.Pro716Leu	missense	Exon 32 of 35	ENSP00000355180.3
	COL6A1	ENST00000498614.5	TSL:1	n.381C>T		non_coding_transcript_exon	Exon 3 of 6
	COL6A1	ENST00000612273.2	TSL:5	c.272C>T	p.Pro91Leu	missense	Exon 3 of 7	ENSP00000483630.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000146 AC: 3 AN: 204838 AF XY: 0.00000894

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000335

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000139 AC: 20 AN: 1441212 Hom.: 0 Cov.: 35 AF XY: 0.0000168 AC XY: 12 AN XY: 715622

African (AFR) AF: 0.00 AC: 0 AN: 33236

American (AMR) AF: 0.0000240 AC: 1 AN: 41662

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25672

East Asian (EAS) AF: 0.00 AC: 0 AN: 38832

South Asian (SAS) AF: 0.0000358 AC: 3 AN: 83766

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48256

Middle Eastern (MID) AF: 0.000874 AC: 5 AN: 5724

European-Non Finnish (NFE) AF: 0.00000724 AC: 8 AN: 1104386

Other (OTH) AF: 0.0000503 AC: 3 AN: 59678

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000828 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Ullrich congenital muscular dystrophy 1A;CN029274:Bethlem myopathy 1A (2)
-	-	1	Bethlem myopathy 1A (1)
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	Ullrich congenital muscular dystrophy 1A (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.046	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.80	T
M_CAP	Uncertain	0.098	D
MetaRNN	Benign	0.27	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.3	L
PhyloP100		0.074
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.27
Sift	Benign	0.11	T
Sift4G	Benign	0.23	T
Polyphen		0.22	B
Vest4		0.41
MutPred		0.50		Loss of glycosylation at P716 (P = 0.0095)
MVP		0.76
MPC		0.74
ClinPred		0.72	D
GERP RS		2.8
Varity_R		0.15
gMVP		0.41
Mutation Taster		=95/5	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: rs755589190; hg19: chr21-47422212;