rs2242264

Variant names:

• chr8-144442022-C-G
• rs2242264
• NM_013432.5:c.865+15G>C

Your query was ambiguous. Multiple possible variants found:

• chr8-144442022-C-G
• chr8-144442022-C-T

Variant summary

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

The NM_013432.5(TONSL):​c.865+15G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.986 in 1,611,010 control chromosomes in the GnomAD database, including 784,273 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.98 (72830 hom., cov: 32)
  • Exomes 𝑓: 0.99 (711443 hom.)
• Consequence: TONSL NM_013432.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.79
• Publications: 6 publications found

Genes affected

TONSL (HGNC:7801): (tonsoku like, DNA repair protein) The protein encoded by this gene is thought to be a negative regulator of NF-kappa-B mediated transcription. The encoded protein may bind NF-kappa-B complexes and trap them in the cytoplasm, preventing them from entering the nucleus and interacting with the DNA. Phosphorylation of this protein targets it for degradation by the ubiquitination pathway, which frees the NF-kappa-B complexes to enter the nucleus. [provided by RefSeq, Jul 2008]

TONSL Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia, sponastrime type

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Ambry Genetics

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BP6: Variant 8-144442022-C-G is Benign according to our data. Variant chr8-144442022-C-G is described in ClinVar as Benign. ClinVar VariationId is 1167011.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.991 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013432.5. 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
	TONSL	NM_013432.5	MANE Select	c.865+15G>C		intron	N/A	NP_038460.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TONSL	ENST00000409379.8	TSL:1 MANE Select	c.865+15G>C		intron	N/A	ENSP00000386239.3
	TONSL	ENST00000497613.2	TSL:2	n.835G>C		non_coding_transcript_exon	Exon 1 of 17

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148688 AN: 152120 Hom.: 72786 Cov.: 32

Gnomad AFR AF: 0.976

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.929

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 0.801

Gnomad SAS AF: 0.997

Gnomad FIN AF: 0.997

Gnomad MID AF: 0.994

Gnomad NFE AF: 0.997

Gnomad OTH AF: 0.977

GnomAD2 exomes AF: 0.965 AC: 239412 AN: 248224 AF XY: 0.971

Gnomad AFR exome AF: 0.976

Gnomad AMR exome AF: 0.887

Gnomad ASJ exome AF: 0.990

Gnomad EAS exome AF: 0.789

Gnomad FIN exome AF: 0.996

Gnomad NFE exome AF: 0.997

Gnomad OTH exome AF: 0.979

GnomAD4 exome AF: 0.987 AC: 1439208 AN: 1458772 Hom.: 711443 Cov.: 35 AF XY: 0.987 AC XY: 716648 AN XY: 725734

African (AFR) AF: 0.978 AC: 32680 AN: 33432

American (AMR) AF: 0.893 AC: 39897 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 25841 AN: 26120

East Asian (EAS) AF: 0.756 AC: 29999 AN: 39682

South Asian (SAS) AF: 0.998 AC: 85993 AN: 86192

European-Finnish (FIN) AF: 0.995 AC: 51883 AN: 52122

Middle Eastern (MID) AF: 0.995 AC: 5316 AN: 5342

European-Non Finnish (NFE) AF: 0.998 AC: 1108210 AN: 1110950

Other (OTH) AF: 0.986 AC: 59389 AN: 60254

GnomAD4 genome AF: 0.977 AC: 148789 AN: 152238 Hom.: 72830 Cov.: 32 AF XY: 0.975 AC XY: 72566 AN XY: 74428

African (AFR) AF: 0.976 AC: 40560 AN: 41552

American (AMR) AF: 0.929 AC: 14199 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 3433 AN: 3472

East Asian (EAS) AF: 0.800 AC: 4127 AN: 5156

South Asian (SAS) AF: 0.997 AC: 4816 AN: 4830

European-Finnish (FIN) AF: 0.997 AC: 10581 AN: 10618

Middle Eastern (MID) AF: 0.993 AC: 292 AN: 294

European-Non Finnish (NFE) AF: 0.997 AC: 67806 AN: 68000

Other (OTH) AF: 0.977 AC: 2063 AN: 2112

Alfa AF: 0.989 Hom.: 13682

Bravo AF: 0.971

Asia WGS AF: 0.936 AC: 3257 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Sponastrime dysplasia (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.97
DANN	Benign	0.33
PhyloP100		-2.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2242264; hg19: chr8-145667405; COSMIC: COSV68048452; COSMIC: COSV68048452;