chr2-165953686-T-TCACCCGC

Variant names:

• chr2-165953686-T-TCACCCGC
• rs759648976
• NM_024753.5:c.19_20insGCGGGTG

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_024753.5(TTC21B):​c.19_20insGCGGGTG​(p.Lys7SerfsTer3) variant causes a frameshift, stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (no stars).

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000018 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTC21B NM_024753.5 frameshift, stop_gained, splice_region
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.359
• Publications: 0 publications found

Genes affected

TTC21B (HGNC:25660): (tetratricopeptide repeat domain 21B) This gene encodes a member of TTC21 family, containing several tetratricopeptide repeat (TPR) domains. This protein is localized to the cilium axoneme, and may play a role in retrograde intraflagellar transport in cilia. Mutations in this gene are associated with various ciliopathies, nephronophthisis 12, and asphyxiating thoracic dystrophy 4. [provided by RefSeq, Oct 2011]

TTC21B Gene-Disease associations (from GenCC):

• nephronophthisis 12

  Inheritance: AD, AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• asphyxiating thoracic dystrophy 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Jeune syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• nephronophthisis 2

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 105 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-165953686-T-TCACCCGC is Pathogenic according to our data. Variant chr2-165953686-T-TCACCCGC is described in CliVar as Likely_pathogenic. Clinvar id is 446699.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165953686-T-TCACCCGC is described in CliVar as Likely_pathogenic. Clinvar id is 446699.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165953686-T-TCACCCGC is described in CliVar as Likely_pathogenic. Clinvar id is 446699.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165953686-T-TCACCCGC is described in CliVar as Likely_pathogenic. Clinvar id is 446699.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165953686-T-TCACCCGC is described in CliVar as Likely_pathogenic. Clinvar id is 446699.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165953686-T-TCACCCGC is described in CliVar as Likely_pathogenic. Clinvar id is 446699.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr2-165953686-T-TCACCCGC is described in CliVar as Likely_pathogenic. Clinvar id is 446699.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.19_20insGCGGGTG	p.Lys7SerfsTer3	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2	c.19_20insGCGGGTG	p.Lys7SerfsTer3	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 28		XP_016860456.1
TTC21B	XM_006712761.2	c.19_20insGCGGGTG	p.Lys7SerfsTer3	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 23		XP_006712824.1
TTC21B	XM_011511872.3	c.19_20insGCGGGTG	p.Lys7SerfsTer3	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 21		XP_011510174.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.19_20insGCGGGTG	p.Lys7SerfsTer3	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 29	1	NM_024753.5	ENSP00000243344.7

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.000128 AC: 7 AN: 54534 AF XY: 0.0000696

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.000132

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000205

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000180 AC: 1 AN: 557014 Hom.: 0 Cov.: 36 AF XY: 0.00000358 AC XY: 1 AN XY: 279130

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12198

American (AMR) AF: 0.00 AC: 0 AN: 11324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10652

East Asian (EAS) AF: 0.00 AC: 0 AN: 21502

South Asian (SAS) AF: 0.00 AC: 0 AN: 39616

European-Finnish (FIN) AF: 0.0000398 AC: 1 AN: 25112

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2740

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 408306

Other (OTH) AF: 0.00 AC: 0 AN: 25564

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 26

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: no assertion criteria provided

Submissions by phenotype

Short-rib thoracic dysplasia 6 with or without polydactyly Pathogenic:2

-

University of Washington Center for Mendelian Genomics, University of Washington

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Jun 01, 2017

Dan Cohn Lab, University Of California Los Angeles

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.36

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs759648976; hg19: chr2-166810196;