rs2163649

Variant names:

• chr2-165924648-G-A
• rs2163649
• NM_024753.5:c.1417C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024753.5(TTC21B):​c.1417C>T​(p.Leu473Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0133 in 1,613,684 control chromosomes in the GnomAD database, including 699 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (124 hom., cov: 32)
  • Exomes 𝑓: 0.013 (575 hom.)
• Consequence: TTC21B NM_024753.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.66
• Publications: 12 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0019389987).
• BP6: Variant 2-165924648-G-A is Benign according to our data. Variant chr2-165924648-G-A is described in ClinVar as Benign. ClinVar VariationId is 96137.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.098 is higher than 0.05.

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.1417C>T	p.Leu473Phe	missense	Exon 12 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.1417C>T	p.Leu473Phe	missense	Exon 12 of 29	ENSP00000243344.7	Q7Z4L5-1
	TTC21B	ENST00000679840.1		c.1417C>T	p.Leu473Phe	missense	Exon 12 of 27	ENSP00000505248.1	A0A7P0T8P4
	TTC21B	ENST00000679799.1		c.1417C>T	p.Leu473Phe	missense	Exon 12 of 28	ENSP00000505208.1	A0A494C0N4

Frequencies

GnomAD3 genomes AF: 0.0184 AC: 2800 AN: 152188 Hom.: 123 Cov.: 32

Gnomad AFR AF: 0.00299

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.102

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.0640

Gnomad SAS AF: 0.00517

Gnomad FIN AF: 0.0239

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00672

Gnomad OTH AF: 0.0158

GnomAD2 exomes AF: 0.0293 AC: 7363 AN: 251288 AF XY: 0.0243

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.132

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.0667

Gnomad FIN exome AF: 0.0231

Gnomad NFE exome AF: 0.00640

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0128 AC: 18719 AN: 1461378 Hom.: 575 Cov.: 31 AF XY: 0.0120 AC XY: 8703 AN XY: 727002

African (AFR) AF: 0.00203 AC: 68 AN: 33460

American (AMR) AF: 0.129 AC: 5773 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00410 AC: 107 AN: 26122

East Asian (EAS) AF: 0.0748 AC: 2962 AN: 39602

South Asian (SAS) AF: 0.00344 AC: 297 AN: 86234

European-Finnish (FIN) AF: 0.0223 AC: 1191 AN: 53398

Middle Eastern (MID) AF: 0.00174 AC: 10 AN: 5762

European-Non Finnish (NFE) AF: 0.00684 AC: 7606 AN: 1111736

Other (OTH) AF: 0.0117 AC: 705 AN: 60358

GnomAD4 genome AF: 0.0184 AC: 2799 AN: 152306 Hom.: 124 Cov.: 32 AF XY: 0.0204 AC XY: 1522 AN XY: 74472

African (AFR) AF: 0.00298 AC: 124 AN: 41578

American (AMR) AF: 0.102 AC: 1563 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.0638 AC: 331 AN: 5188

South Asian (SAS) AF: 0.00497 AC: 24 AN: 4830

European-Finnish (FIN) AF: 0.0239 AC: 253 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00672 AC: 457 AN: 68022

Other (OTH) AF: 0.0151 AC: 32 AN: 2116

Alfa AF: 0.0113 Hom.: 86

Bravo AF: 0.0243

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.00363 AC: 16

ESP6500EA AF: 0.00767 AC: 66

ExAC AF: 0.0237 AC: 2877

Asia WGS AF: 0.0290 AC: 99 AN: 3476

EpiCase AF: 0.00677

EpiControl AF: 0.00581

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	1	Asphyxiating thoracic dystrophy 4 (1)
-	-	1	Connective tissue disorder (1)
-	-	1	Jeune thoracic dystrophy;C0687120:Nephronophthisis (1)
-	-	1	Nephronophthisis 12 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	12
DANN	Uncertain	0.99
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.71	T
MetaRNN	Benign	0.0019	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.7
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.11
Sift	Benign	0.059	T
Sift4G	Benign	0.12	T
Polyphen		0.0030	B
Vest4		0.030
MPC		0.032
ClinPred		0.0078	T
GERP RS		1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.095
gMVP		0.32
Mutation Taster		=94/6	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs2163649; hg19: chr2-166781158; COSMIC: COSV99691925; COSMIC: COSV99691925;