rs797046038

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 1P and 9B. PM4_SupportingBP6BS1BS2

The NM_001082538.3(TCTN1):c.702_704delTAA(p.Asn235del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.003 in 1,613,986 control chromosomes in the GnomAD database, including 8 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0017 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0031 ( 7 hom. )

Consequence

TCTN1
NM_001082538.3 disruptive_inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:5

Conservation

PhyloP100: 5.66

Publications

2 publications found

Variant links:

Genes affected

TCTN1 (HGNC:26113): (tectonic family member 1) This gene encodes a member of a family of secreted and transmembrane proteins. The orthologous gene in mouse functions downstream of smoothened and rab23 to modulate hedgehog signal transduction. This protein is a component of the tectonic-like complex, which forms a barrier between the ciliary axoneme and the basal body. A mutation in this gene was found in a family with Joubert syndrome-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

TCTN1 links:

HVCN1 (HGNC:28240): (hydrogen voltage gated channel 1) This gene encodes a voltage-gated protein channel protein expressed more highly in certain cells of the immune system. Phagocytic cells produce superoxide anions which require this channel protein, and in B cells this same process facilitates antibody production. This same channel protein, however, can also regulate functions in other cells including spermatozoa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

HVCN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PM4

Nonframeshift variant in NON repetitive region in NM_001082538.3. Strenght limited to Supporting due to length of the change: 1aa.

BP6

Variant 12-110632544-GATA-G is Benign according to our data. Variant chr12-110632544-GATA-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 212385.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00171 (260/152310) while in subpopulation NFE AF = 0.00331 (225/68028). AF 95% confidence interval is 0.00295. There are 1 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3 link	c.702_704delTAA	p.Asn235del	disruptive_inframe_deletion	Exon 5 of 15	ENST00000397659.9	NP_001076007.1	Q2MV58-2B4DIB9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
TCTN1	ENST00000397659.9 link	c.702_704delTAA	p.Asn235del	disruptive_inframe_deletion	Exon 5 of 15	1	NM_001082538.3	ENSP00000380779.4	Q2MV58-2
TCTN1	ENST00000551590.5 link	c.702_704delTAA	p.Asn235del	disruptive_inframe_deletion	Exon 5 of 15	1		ENSP00000448735.1	Q2MV58-1
TCTN1	ENST00000397655.7 link	c.702_704delTAA	p.Asn235del	disruptive_inframe_deletion	Exon 5 of 15	1		ENSP00000380775.3	Q2MV58-3
TCTN1	ENST00000397656.8 link	n.335_337delTAA		non_coding_transcript_exon_variant	Exon 6 of 16	2		ENSP00000380776.4	J3KPW2
TCTN1	ENST00000480648.5 link	n.702_704delTAA		non_coding_transcript_exon_variant	Exon 5 of 16	5		ENSP00000437196.1	E9PNE4
TCTN1	ENST00000495659.6 link	n.460_462delTAA		non_coding_transcript_exon_variant	Exon 5 of 15	2		ENSP00000436673.2	E9PIB8
TCTN1	ENST00000397656.8 link	n.335_337delTAA		3_prime_UTR_variant	Exon 6 of 16	2		ENSP00000380776.4	J3KPW2
TCTN1	ENST00000495659.6 link	n.460_462delTAA		3_prime_UTR_variant	Exon 5 of 15	2		ENSP00000436673.2	E9PIB8

Frequencies

GnomAD3 genomes

AF:

0.00171

AC:

260

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000262

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00331

Gnomad OTH

AF:

0.00144

GnomAD2 exomes

AF:

0.00160

AC:

400

AN:

249536

AF XY:

0.00154

show subpopulations

Gnomad AFR exome

AF:

0.000323

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000418

Gnomad NFE exome

AF:

0.00333

Gnomad OTH exome

AF:

0.000825

GnomAD4 exome

AF:

0.00313

AC:

4576

AN:

1461676

Hom.:

AF XY:

0.00297

AC XY:

2158

AN XY:

727174

show subpopulations

African (AFR)

AF:

0.000299

AC:

AN:

33466

American (AMR)

AF:

0.000112

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.000805

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00398

AC:

4424

AN:

1111882

Other (OTH)

AF:

0.00154

AC:

AN:

60382

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

244

488

733

977

1221

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

168

336

504

672

840

<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

AF:

0.00171

AC:

260

AN:

152310

Hom.:

Cov.:

AF XY:

0.00157

AC XY:

117

AN XY:

74480

show subpopulations

African (AFR)

AF:

0.000553

AC:

AN:

41560

American (AMR)

AF:

0.000261

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00331

AC:

225

AN:

68028

Other (OTH)

AF:

0.00142

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.488

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.000613

Hom.:

Bravo

AF:

0.00156

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00294

EpiControl

AF:

0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:1

Oct 21, 2016

Eurofins Ntd Llc (ga)

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Department of Pathology and Laboratory Medicine, Sinai Health System

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

The TCTN1 p.Asn235del variant was not identified in the literature nor was it identified in LOVD 3.0. The variant was identified in dbSNP (ID: rs1179582623) and ClinVar (classified as uncertain significance by Genetic Services Laboratory, University of Chicago, EGL Genetic Diagnostics and GeneDx, and as likely benign by Invitae). The variant was identified in control databases in 455 of 280942 chromosomes (2 homozygous) at a frequency of 0.00162 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database March 6, 2019, v2.1.1). The variant was observed in the following populations: European (non-Finnish) in 420 of 128690 chromosomes (freq: 0.003264), Other in 7 of 7148 chromosomes (freq: 0.000979), European (Finnish) in 12 of 25030 chromosomes (freq: 0.000479), African in 11 of 24202 chromosomes (freq: 0.000455) and Latino in 5 of 35374 chromosomes (freq: 0.000141), but was not observed in the Ashkenazi Jewish, East Asian, or South Asian populations. This variant is an in-frame deletion resulting in the removal of a asparagine (asn) residue at codon 235; the impact of this alteration on TCTN1 protein function is not known. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign. -

Sep 04, 2018

GeneDx

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

A variant of uncertain significance has been identified in the TCTN1 gene. The c.702_704delTAA variant has not been published as a pathogenic variant, nor has it been reported as a benign variant to our knowledge. The c.702_704delTAA variant is observed in 168/66,738 (0.3%) alleles from individuals of European background (Lek et al., 2016; 1000 Genomes Consortium et al., 2015; Exome Variant Server). The c.702_704delTAA results in an in-frame deletion of a single Asparagine residue, denoted p.Asn235del. Based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant. -

TCTN1-related disorder

Benign:1

Feb 03, 2022

PreventionGenetics, part of Exact Sciences

Significance:Likely benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not specified

Benign:1

Feb 08, 2021

Genetic Services Laboratory, University of Chicago

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

Apr 19, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Meckel-Gruber syndrome;C0431399:Joubert syndrome

Benign:1

Jan 20, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

5.7

Mutation Taster

=84/16

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over