chr2-165953686-T-TCACCCGC

Position:

• chr2-165953686-T-TCACCCGC

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The ENST00000243344.8(TTC21B):​c.19_20insGCGGGTG​(p.Lys7SerfsTer3) variant causes a stop gained, frameshift, 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 ENST00000243344.8 stop_gained, frameshift, splice_region
• Clinical Significance: Likely pathogenic no assertion criteria provided P:2
• Conservation: PhyloP100: 0.359

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]

ACMG classification

Verdict is Pathogenic. Variant got 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 73 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 ClinVar 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/exons	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.19_20insGCGGGTG	p.Lys7SerfsTer3	stop_gained, frameshift_variant, splice_region_variant	1/29	ENST00000243344.8	NP_079029.3
TTC21B	XM_006712761.2	c.19_20insGCGGGTG	p.Lys7SerfsTer3	stop_gained, frameshift_variant, splice_region_variant	1/23		XP_006712824.1
TTC21B	XM_011511872.3	c.19_20insGCGGGTG	p.Lys7SerfsTer3	stop_gained, frameshift_variant, splice_region_variant	1/21		XP_011510174.1
TTC21B	XM_017004967.2	c.19_20insGCGGGTG	p.Lys7SerfsTer3	stop_gained, frameshift_variant, splice_region_variant	1/28		XP_016860456.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTC21B	ENST00000243344.8	c.19_20insGCGGGTG	p.Lys7SerfsTer3	stop_gained, frameshift_variant, splice_region_variant	1/29	1	NM_024753.5	ENSP00000243344	P1

Frequencies

GnomAD3 genomes Cov.: 26

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000398

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

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

Likely pathogenic, no assertion criteria provided	research	University of Washington Center for Mendelian Genomics, University of Washington	-	- -
Likely pathogenic, no assertion criteria provided	research	Dan Cohn Lab, University Of California Los Angeles	Jun 01, 2017	- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs759648976; hg19: chr2-166810196;