rs797046038

chr12-110632544-GATA-Gchr12-110632544-GATA-GATAATA

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS1

The NM_001082538.3(TCTN1):c.702_704del(p.Asn235del) variant causes a 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 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• Conservation: PhyloP100: 5.66

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]

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 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 id is 212385.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=4}. Variant chr12-110632544-GATA-G is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN1	NM_001082538.3	c.702_704del	p.Asn235del	inframe_deletion	5/15	ENST00000397659.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN1	ENST00000397659.9	c.702_704del	p.Asn235del	inframe_deletion	5/15	1	NM_001082538.3	A1

Frequencies

GnomAD3 genomes AF: 0.00171 AC: 260 AN: 152192 Hom.: 1 Cov.: 32

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

GnomAD3 exomes AF: 0.00160 AC: 400 AN: 249536 Hom.: 1 AF XY: 0.00154 AC XY: 208 AN XY: 135382

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 SAS 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.: 7 AF XY: 0.00297 AC XY: 2158 AN XY: 727174

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.000805

Gnomad4 NFE exome AF: 0.00398

Gnomad4 OTH exome AF: 0.00154

GnomAD4 genome AF: 0.00171 AC: 260 AN: 152310 Hom.: 1 Cov.: 32 AF XY: 0.00157 AC XY: 117 AN XY: 74480

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.000261

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000471

Gnomad4 NFE AF: 0.00331

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.000613 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00294

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, no assertion criteria provided	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	-	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 04, 2018	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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 21, 2016	- -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

TCTN1-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 03, 2022

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

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2021

- -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 19, 2022

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. -

Computational scores

Source: dbNSFP v4.3

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

Other links and lift over

dbSNP: rs797046038; hg19: chr12-111070349;