2-165953686-T-TCACCCGCTCACCCGC

Variant names:

• chr2-165953686-T-TCACCCGCTCACCCGC
• rs759648976
• NM_024753.5:c.19_20insGCGGGTGAGCGGGTG

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1

The NM_024753.5(TTC21B):​c.19_20insGCGGGTGAGCGGGTG​(p.Lys7delinsSerGlyTerAlaGlyGlu) variant causes a stop gained, conservative inframe insertion, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000177 in 56,570 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type INS_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000018 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0000072 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: TTC21B NM_024753.5 stop_gained, conservative_inframe_insertion, splice_region
• Clinical Significance: Not reported in ClinVar
• 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: Likely_pathogenic. The variant received 8 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5	c.19_20insGCGGGTGAGCGGGTG	p.Lys7delinsSerGlyTerAlaGlyGlu	stop_gained, conservative_inframe_insertion, splice_region_variant	Exon 1 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2	c.19_20insGCGGGTGAGCGGGTG	p.Lys7delinsSerGlyTerAlaGlyGlu	stop_gained, conservative_inframe_insertion, splice_region_variant	Exon 1 of 28		XP_016860456.1
TTC21B	XM_006712761.2	c.19_20insGCGGGTGAGCGGGTG	p.Lys7delinsSerGlyTerAlaGlyGlu	stop_gained, conservative_inframe_insertion, splice_region_variant	Exon 1 of 23		XP_006712824.1
TTC21B	XM_011511872.3	c.19_20insGCGGGTGAGCGGGTG	p.Lys7delinsSerGlyTerAlaGlyGlu	stop_gained, conservative_inframe_insertion, 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_20insGCGGGTGAGCGGGTG	p.Lys7delinsSerGlyTerAlaGlyGlu	stop_gained, conservative_inframe_insertion, splice_region_variant	Exon 1 of 29	1	NM_024753.5	ENSP00000243344.7

Frequencies

GnomAD3 genomes AF: 0.0000177 AC: 1 AN: 56570 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000713

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000718 AC: 4 AN: 556982 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 279116

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

African (AFR) AF: 0.000329 AC: 4 AN: 12174

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: 0.00 AC: 0 AN: 25112

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 408302

Other (OTH) AF: 0.00 AC: 0 AN: 25560

⚠️ 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 AF: 0.0000177 AC: 1 AN: 56570 Hom.: 0 Cov.: 26 AF XY: 0.0000361 AC XY: 1 AN XY: 27698

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

African (AFR) AF: 0.0000713 AC: 1 AN: 14024

American (AMR) AF: 0.00 AC: 0 AN: 5442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1486

East Asian (EAS) AF: 0.00 AC: 0 AN: 2210

South Asian (SAS) AF: 0.00 AC: 0 AN: 1966

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3502

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 130

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 26662

Other (OTH) AF: 0.00 AC: 0 AN: 806

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

ClinVar

Not reported in ClinVar

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;