chr2-165953686-T-TCACCCGCTCACCA

Variant names:

• chr2-165953686-T-TCACCCGCTCACCA
• rs759648976
• NM_024753.5:c.19_20insTGGTGAGCGGGTG

Variant summary

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

The NM_024753.5(TTC21B):​c.19_20insTGGTGAGCGGGTG​(p.Lys7MetfsTer5) variant causes a frameshift, stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000718 in 557,014 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: not found (cov: 26)
  • Exomes 𝑓: 0.0000072 (0 hom.)
• Consequence: TTC21B NM_024753.5 frameshift, stop_gained, 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_20insTGGTGAGCGGGTG	p.Lys7MetfsTer5	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2	c.19_20insTGGTGAGCGGGTG	p.Lys7MetfsTer5	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 28		XP_016860456.1
TTC21B	XM_006712761.2	c.19_20insTGGTGAGCGGGTG	p.Lys7MetfsTer5	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 23		XP_006712824.1
TTC21B	XM_011511872.3	c.19_20insTGGTGAGCGGGTG	p.Lys7MetfsTer5	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_20insTGGTGAGCGGGTG	p.Lys7MetfsTer5	frameshift_variant, stop_gained, splice_region_variant	Exon 1 of 29	1	NM_024753.5	ENSP00000243344.7

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD4 exome AF: 0.00000718 AC: 4 AN: 557014 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 279128

⚠️ 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: 12208

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

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 10650

East Asian (EAS) AF: 0.0000465 AC: 1 AN: 21502

South Asian (SAS) AF: 0.00 AC: 0 AN: 39614

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: 0.00000735 AC: 3 AN: 408300

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

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;