Genetic Variant NM_024753.5:c.19_20insGGGTG (chr2-165953686-T-TCACCC) – ACMG Classification: Pathogenic (10 pts)

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1PM2

The NM_024753.5(TTC21B):c.19_20insGGGTG(p.Lys7ArgfsTer5) variant causes a frameshift, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000898 in 557,028 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 26)

Exomes 𝑓: 0.0000090 ( 0 hom. )

Consequence

TTC21B
NM_024753.5 frameshift, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.359

Publications

0 publications found

Variant links:

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

TTC21B links:

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ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 10 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;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TTC21B	NM_024753.5 link	c.19_20insGGGTG	p.Lys7ArgfsTer5	frameshift_variant, splice_region_variant	Exon 1 of 29	ENST00000243344.8	NP_079029.3
TTC21B	XM_017004967.2 link	c.19_20insGGGTG	p.Lys7ArgfsTer5	frameshift_variant, splice_region_variant	Exon 1 of 28		XP_016860456.1	A0A7P0TB61
TTC21B	XM_006712761.2 link	c.19_20insGGGTG	p.Lys7ArgfsTer5	frameshift_variant, splice_region_variant	Exon 1 of 23		XP_006712824.1	A0A7P0TA66
TTC21B	XM_011511872.3 link	c.19_20insGGGTG	p.Lys7ArgfsTer5	frameshift_variant, 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 link	c.19_20insGGGTG	p.Lys7ArgfsTer5	frameshift_variant, splice_region_variant	Exon 1 of 29	1	NM_024753.5	ENSP00000243344.7		Q7Z4L5-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

54534

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000898

AC:

AN:

557028

Hom.:

Cov.:

AF XY:

0.0000107

AC XY:

AN XY:

279136

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

12208

American (AMR)

AF:

0.00

AC:

AN:

11324

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

10652

East Asian (EAS)

AF:

0.00

AC:

AN:

21502

South Asian (SAS)

AF:

0.00

AC:

AN:

39616

European-Finnish (FIN)

AF:

0.00

AC:

AN:

25112

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2740

European-Non Finnish (NFE)

AF:

0.0000122

AC:

AN:

408310

Other (OTH)

AF:

0.00

AC:

AN:

25564

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over