rs375721812

Variant names:

• chr2-165953687-T-C
• rs375721812
• NM_024753.5:c.19A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_024753.5(TTC21B):​c.19A>G​(p.Lys7Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00126 in 794,418 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 26)
  • Exomes 𝑓: 0.0013 (0 hom.)
• Consequence: TTC21B NM_024753.5 missense, splice_region
• Scores: Splicing: ADA: 0.004587
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:7
• 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):

• asphyxiating thoracic dystrophy 4

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• nephronophthisis 12

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

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.016642302).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024753.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	NM_024753.5	MANE Select	c.19A>G	p.Lys7Glu	missense splice_region	Exon 1 of 29	NP_079029.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTC21B	ENST00000243344.8	TSL:1 MANE Select	c.19A>G	p.Lys7Glu	missense splice_region	Exon 1 of 29	ENSP00000243344.7	Q7Z4L5-1
	TTC21B	ENST00000464374.5	TSL:1	n.59A>G		splice_region non_coding_transcript_exon	Exon 1 of 11
	TTC21B	ENST00000679840.1		c.19A>G	p.Lys7Glu	missense splice_region	Exon 1 of 27	ENSP00000505248.1	A0A7P0T8P4

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 84 AN: 71062 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.000375

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000275

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: 0.00219

Gnomad OTH AF: 0.00103

GnomAD2 exomes AF: 0.000661 AC: 43 AN: 65090 AF XY: 0.000759

Gnomad AFR exome AF: 0.000602

Gnomad AMR exome AF: 0.000292

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00147

Gnomad OTH exome AF: 0.00161

GnomAD4 exome AF: 0.00127 AC: 918 AN: 723314 Hom.: 0 Cov.: 36 AF XY: 0.00116 AC XY: 415 AN XY: 358398

African (AFR) AF: 0.000145 AC: 2 AN: 13812

American (AMR) AF: 0.000334 AC: 5 AN: 14972

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 12892

East Asian (EAS) AF: 0.00 AC: 0 AN: 25410

South Asian (SAS) AF: 0.0000214 AC: 1 AN: 46790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3184

European-Non Finnish (NFE) AF: 0.00159 AC: 869 AN: 544858

Other (OTH) AF: 0.00129 AC: 41 AN: 31734

GnomAD4 genome AF: 0.00118 AC: 84 AN: 71104 Hom.: 0 Cov.: 26 AF XY: 0.00118 AC XY: 41 AN XY: 34790

African (AFR) AF: 0.000374 AC: 6 AN: 16034

American (AMR) AF: 0.000274 AC: 2 AN: 7290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1816

East Asian (EAS) AF: 0.00 AC: 0 AN: 2872

South Asian (SAS) AF: 0.00 AC: 0 AN: 2430

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4874

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

European-Non Finnish (NFE) AF: 0.00219 AC: 75 AN: 34262

Other (OTH) AF: 0.00102 AC: 1 AN: 982

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000506

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000437 AC: 2

ExAC AF: 0.000194 AC: 5

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	-	Asphyxiating thoracic dystrophy 4 (1)
-	1	-	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	1	-	Nephronophthisis 12 (1)
-	1	-	TTC21B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	17
DANN	Benign	0.94
DEOGEN2	Benign	0.063	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.61	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.017	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		0.36
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-0.35	N
REVEL	Benign	0.19
Sift	Benign	0.22	T
Sift4G	Benign	1.0	T
Polyphen		0.025	B
Vest4		0.43
MVP		0.22
MPC		0.037
ClinPred		0.039	T
GERP RS		3.4
PromoterAI		0.012	Neutral
Varity_R		0.21
gMVP		0.13
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0046
dbscSNV1_RF	Benign	0.080
SpliceAI score (max)		0.080		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs375721812; hg19: chr2-166810197;