rs16940927

chr12-110640433-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001082538.3(TCTN1):c.894C>T(p.Leu298=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00346 in 1,614,132 control chromosomes in the GnomAD database, including 166 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (89 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (77 hom.)
• Consequence: TCTN1 NM_001082538.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.27

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 12-110640433-C-T is Benign according to our data. Variant chr12-110640433-C-T is described in ClinVar as [Benign]. Clinvar id is 160099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110640433-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.27 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0596 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN1	NM_001082538.3	c.894C>T	p.Leu298=	synonymous_variant	8/15	ENST00000397659.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN1	ENST00000397659.9	c.894C>T	p.Leu298=	synonymous_variant	8/15	1	NM_001082538.3	A1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2711 AN: 152126 Hom.: 90 Cov.: 32

Gnomad AFR AF: 0.0617

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00701

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000367

Gnomad OTH AF: 0.0120

GnomAD3 exomes AF: 0.00498 AC: 1243 AN: 249570 Hom.: 43 AF XY: 0.00383 AC XY: 518 AN XY: 135402

Gnomad AFR exome AF: 0.0667

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000980

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.00412

GnomAD4 exome AF: 0.00197 AC: 2873 AN: 1461886 Hom.: 77 Cov.: 31 AF XY: 0.00168 AC XY: 1220 AN XY: 727242

Gnomad4 AFR exome AF: 0.0636

Gnomad4 AMR exome AF: 0.00510

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000205

Gnomad4 OTH exome AF: 0.00409

GnomAD4 genome AF: 0.0178 AC: 2717 AN: 152246 Hom.: 89 Cov.: 32 AF XY: 0.0172 AC XY: 1280 AN XY: 74454

Gnomad4 AFR AF: 0.0616

Gnomad4 AMR AF: 0.00700

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000368

Gnomad4 OTH AF: 0.0119

Alfa AF: 0.00526 Hom.: 19

Bravo AF: 0.0207

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000491

EpiControl AF: 0.000711

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 26, 2024

- -

Joubert syndrome 13 Benign:1

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	0.32
Dann	Benign	0.85

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: rs16940927; hg19: chr12-111078238;