12-123686886-C-T

Position:

chr12-123686886-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP6BS1

The NM_024809.5(TCTN2):c.615C>T(p.Gly205Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000655 in 1,614,180 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00059 ( 1 hom. )

Consequence

TCTN2
NM_024809.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3B:5

Conservation

PhyloP100: -1.94

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 -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP6

Variant 12-123686886-C-T is Benign according to our data. Variant chr12-123686886-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 198262.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=3, Benign=1}. Variant chr12-123686886-C-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00131 (200/152292) while in subpopulation AFR AF= 0.00368 (153/41562). AF 95% confidence interval is 0.00321. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN2	NM_024809.5 linkuse as main transcript	c.615C>T	p.Gly205Gly	synonymous_variant	6/18	ENST00000303372.7	NP_079085.2	Q96GX1-1
TCTN2	NM_001143850.3 linkuse as main transcript	c.612C>T	p.Gly204Gly	synonymous_variant	6/18		NP_001137322.1	Q96GX1-2
TCTN2	NM_001410989.1 linkuse as main transcript	c.615C>T	p.Gly205Gly	synonymous_variant	6/17		NP_001397918.1
TCTN2	XM_017019974.2 linkuse as main transcript	c.612C>T	p.Gly204Gly	synonymous_variant	6/17		XP_016875463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7 linkuse as main transcript	c.615C>T	p.Gly205Gly	synonymous_variant	6/18	1	NM_024809.5	ENSP00000304941.5		Q96GX1-1

Frequencies

GnomAD3 genomes

AF:

0.00131

AC:

200

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00369

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00184

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:

0.000206

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000644

AC:

162

AN:

251492

Hom.:

AF XY:

0.000537

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00394

Gnomad AMR exome

AF:

0.00110

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000413

Gnomad OTH exome

AF:

0.00130

GnomAD4 exome

AF:

0.000587

AC:

858

AN:

1461888

Hom.:

Cov.:

AF XY:

0.000532

AC XY:

387

AN XY:

727244

show subpopulations

Gnomad4 AFR exome

AF:

0.00427

Gnomad4 AMR exome

AF:

0.00132

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000519

Gnomad4 OTH exome

AF:

0.000993

GnomAD4 genome

AF:

0.00131

AC:

200

AN:

152292

Hom.:

Cov.:

AF XY:

0.00128

AC XY:

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00368

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000206

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000956

Hom.:

Bravo

AF:

0.00152

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000545

EpiControl

AF:

0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:3

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2024	TCTN2: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	May 05, 2021	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes splice predictors and evolutionary conservation, suggests this variant may impact gene splicing. In the absence of RNA/functional studies, the actual effect of this sequence change is unknown. -

Joubert syndrome 24

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Meckel syndrome, type 8

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 05, 2015

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.55

CADD

Benign

4.5

DANN

Benign

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.28

Position offset: -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