3-130560427-C-T

Variant names:

• chr3-130560427-C-T
• rs76315272
• NM_001102608.3:c.63C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001102608.3(COL6A6):​c.63C>T​(p.Ser21Ser) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00809 in 1,607,194 control chromosomes in the GnomAD database, including 106 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 0.013 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0076 (69 hom.)
• Consequence: COL6A6 NM_001102608.3 splice_region, synonymous
• Scores: Splicing: ADA: 0.0001597
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.304
• Publications: 3 publications found

Genes affected

COL6A6 (HGNC:27023): (collagen type VI alpha 6 chain) This gene encodes a large protein that contains multiple von Willebrand factor domains and forms a component of the basal lamina of epithelial cells. This protein may regulate epithelial cell-fibronectin interactions. Variation in this gene may be implicated in skin diseases. [provided by RefSeq, May 2017]

COL6A6 Gene-Disease associations (from GenCC):

• congenital myopathy

  Inheritance: AR Classification: LIMITED Submitted by: Broad Center for Mendelian Genomics
• myopathy

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 3-130560427-C-T is Benign according to our data. Variant chr3-130560427-C-T is described in ClinVar as Benign. ClinVar VariationId is 773137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.304 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1976/152108) while in subpopulation AFR AF = 0.0318 (1319/41468). AF 95% confidence interval is 0.0304. There are 37 homozygotes in GnomAd4. There are 890 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 37 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001102608.3. 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
	COL6A6	NM_001102608.3	MANE Select	c.63C>T	p.Ser21Ser	splice_region synonymous	Exon 2 of 37	NP_001096078.1	A6NMZ7-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL6A6	ENST00000358511.11	TSL:5 MANE Select	c.63C>T	p.Ser21Ser	splice_region synonymous	Exon 2 of 37	ENSP00000351310.6	A6NMZ7-1

Frequencies

GnomAD3 genomes AF: 0.0130 AC: 1974 AN: 151990 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0319

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.00786

Gnomad ASJ AF: 0.00979

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000623

Gnomad FIN AF: 0.000284

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00678

Gnomad OTH AF: 0.0144

GnomAD2 exomes AF: 0.00646 AC: 1592 AN: 246270 AF XY: 0.00564

Gnomad AFR exome AF: 0.0315

Gnomad AMR exome AF: 0.00558

Gnomad ASJ exome AF: 0.00859

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000749

Gnomad NFE exome AF: 0.00680

Gnomad OTH exome AF: 0.00688

GnomAD4 exome AF: 0.00757 AC: 11020 AN: 1455086 Hom.: 69 Cov.: 29 AF XY: 0.00728 AC XY: 5267 AN XY: 723756

African (AFR) AF: 0.0305 AC: 1015 AN: 33236

American (AMR) AF: 0.00595 AC: 263 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00968 AC: 252 AN: 26020

East Asian (EAS) AF: 0.0000254 AC: 1 AN: 39430

South Asian (SAS) AF: 0.000576 AC: 49 AN: 85030

European-Finnish (FIN) AF: 0.000886 AC: 47 AN: 53032

Middle Eastern (MID) AF: 0.00486 AC: 28 AN: 5756

European-Non Finnish (NFE) AF: 0.00806 AC: 8932 AN: 1108242

Other (OTH) AF: 0.00720 AC: 433 AN: 60106

GnomAD4 genome AF: 0.0130 AC: 1976 AN: 152108 Hom.: 37 Cov.: 33 AF XY: 0.0120 AC XY: 890 AN XY: 74366

African (AFR) AF: 0.0318 AC: 1319 AN: 41468

American (AMR) AF: 0.00785 AC: 120 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00979 AC: 34 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.000623 AC: 3 AN: 4812

European-Finnish (FIN) AF: 0.000284 AC: 3 AN: 10578

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

European-Non Finnish (NFE) AF: 0.00680 AC: 462 AN: 67988

Other (OTH) AF: 0.0142 AC: 30 AN: 2110

Alfa AF: 0.00890 Hom.: 21

Bravo AF: 0.0145

Asia WGS AF: 0.00173 AC: 6 AN: 3472

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	-0.55
CADD	Benign	11
DANN	Benign	0.42
PhyloP100		0.30
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.088
SpliceAI score (max)		0.010		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: rs76315272; hg19: chr3-130279271;