12-123671247-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024809.5(TCTN2):c.7T>C(p.Phe3Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

TCTN2
NM_024809.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.102

Variant links:

Genes affected

TCTN2 (HGNC:25774): (tectonic family member 2) This gene encodes a type I membrane protein that belongs to the tectonic family. Studies in mice suggest that this protein may be involved in hedgehog signaling, and essential for ciliogenesis. Mutations in this gene are associated with Meckel syndrome type 8. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

TCTN2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.046985835).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
TCTN2	NM_024809.5 linkuse as main transcript	c.7T>C	p.Phe3Leu	missense_variant	1/18	ENST00000303372.7
TCTN2	NM_001143850.3 linkuse as main transcript	c.7T>C	p.Phe3Leu	missense_variant	1/18
TCTN2	NM_001410989.1 linkuse as main transcript	c.7T>C	p.Phe3Leu	missense_variant	1/17
TCTN2	XM_017019974.2 linkuse as main transcript	c.7T>C	p.Phe3Leu	missense_variant	1/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN2	ENST00000303372.7 linkuse as main transcript	c.7T>C	p.Phe3Leu	missense_variant	1/18	1	NM_024809.5	P4	Q96GX1-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000403

AC:

AN:

247914

Hom.:

AF XY:

0.00

AC XY:

AN XY:

134462

show subpopulations

Gnomad AFR exome

AF:

0.0000629

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS 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:

0.00000205

AC:

AN:

1460818

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726672

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 13, 2022

This sequence change replaces phenylalanine, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 3 of the TCTN2 protein (p.Phe3Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TCTN2-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0". The leucine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.070

BayesDel_noAF

Benign

-0.34

Cadd

Benign

8.0

Dann

Benign

0.93

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.010

LIST_S2

Benign

0.36

T;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.047

T;T

MetaSVM

Benign

-0.89

MutationAssessor

Benign

0.34

N;N

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.80

N;N

REVEL

Benign

0.21

Sift

Benign

0.79

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

.;B

Vest4

0.019

MutPred

0.27

Gain of catalytic residue at M1 (P = 0);Gain of catalytic residue at M1 (P = 0);

MVP

0.60

MPC

0.16

ClinPred

0.062

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.12

gMVP

0.23

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over