12-110645031-G-T

Variant names:

• chr12-110645031-G-T
• rs118096349
• NM_001082538.3:c.1396G>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001082538.3(TCTN1):​c.1396G>T​(p.Gly466Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0232 in 1,614,174 control chromosomes in the GnomAD database, including 579 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.017 (37 hom., cov: 32)
  • Exomes 𝑓: 0.024 (542 hom.)
• Consequence: TCTN1 NM_001082538.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.63

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0045828223).
• BP6: Variant 12-110645031-G-T is Benign according to our data. Variant chr12-110645031-G-T is described in ClinVar as [Benign]. Clinvar id is 160095.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-110645031-G-T is described in Lovd as [Benign]. Variant chr12-110645031-G-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.051 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.1396G>T	p.Gly466Cys	missense_variant	Exon 12 of 15	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.1396G>T	p.Gly466Cys	missense_variant	Exon 12 of 15	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.1396G>T	p.Gly466Cys	missense_variant	Exon 12 of 15	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.1354G>T	p.Gly452Cys	missense_variant	Exon 12 of 15	1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.*1029G>T		non_coding_transcript_exon_variant	Exon 13 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.*672G>T		non_coding_transcript_exon_variant	Exon 13 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*1154G>T		non_coding_transcript_exon_variant	Exon 12 of 15	2		ENSP00000436673.2
TCTN1	ENST00000397656.8	n.*1029G>T		3_prime_UTR_variant	Exon 13 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.*672G>T		3_prime_UTR_variant	Exon 13 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*1154G>T		3_prime_UTR_variant	Exon 12 of 15	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes AF: 0.0166 AC: 2532 AN: 152174 Hom.: 36 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0184

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.0146

Gnomad SAS AF: 0.0569

Gnomad FIN AF: 0.00867

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0236

Gnomad OTH AF: 0.00862

GnomAD3 exomes AF: 0.0214 AC: 5338 AN: 249560 Hom.: 106 AF XY: 0.0228 AC XY: 3086 AN XY: 135398

Gnomad AFR exome AF: 0.00368

Gnomad AMR exome AF: 0.0141

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0118

Gnomad SAS exome AF: 0.0522

Gnomad FIN exome AF: 0.0110

Gnomad NFE exome AF: 0.0230

Gnomad OTH exome AF: 0.0195

GnomAD4 exome AF: 0.0239 AC: 34883 AN: 1461882 Hom.: 542 Cov.: 30 AF XY: 0.0244 AC XY: 17762 AN XY: 727242

Gnomad4 AFR exome AF: 0.00370

Gnomad4 AMR exome AF: 0.0143

Gnomad4 ASJ exome AF: 0.00230

Gnomad4 EAS exome AF: 0.0106

Gnomad4 SAS exome AF: 0.0505

Gnomad4 FIN exome AF: 0.0114

Gnomad4 NFE exome AF: 0.0247

Gnomad4 OTH exome AF: 0.0189

GnomAD4 genome AF: 0.0166 AC: 2535 AN: 152292 Hom.: 37 Cov.: 32 AF XY: 0.0176 AC XY: 1310 AN XY: 74468

Gnomad4 AFR AF: 0.00399

Gnomad4 AMR AF: 0.0184

Gnomad4 ASJ AF: 0.00173

Gnomad4 EAS AF: 0.0137

Gnomad4 SAS AF: 0.0565

Gnomad4 FIN AF: 0.00867

Gnomad4 NFE AF: 0.0236

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0157 Hom.: 10

Bravo AF: 0.0161

TwinsUK AF: 0.0272 AC: 101

ALSPAC AF: 0.0272 AC: 105

ESP6500AA AF: 0.00397 AC: 15

ESP6500EA AF: 0.0211 AC: 173

ExAC AF: 0.0229 AC: 2769

Asia WGS AF: 0.0290 AC: 102 AN: 3478

EpiCase AF: 0.0187

EpiControl AF: 0.0181

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

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

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Joubert syndrome 13 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
AlphaMissense	Benign	0.23
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	.;T;.;.;.
Eigen	Benign	-0.023
Eigen_PC	Benign	0.0073
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.82	T;T;T;T;T
MetaRNN	Benign	0.0046	T;T;T;T;T
MetaSVM	Uncertain	-0.21	T
MutationAssessor	Uncertain	2.2	.;M;.;M;.
PrimateAI	Benign	0.29	T
PROVEAN	Uncertain	-3.0	.;D;D;D;.
REVEL	Uncertain	0.43
Sift	Uncertain	0.014	.;D;D;D;.
Sift4G	Benign	0.088	T;T;T;T;T
Polyphen		1.0, 1.0	.;D;D;D;.
Vest4		0.10
MPC		0.70
ClinPred		0.014	T
GERP RS		3.5
Varity_R		0.16
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs118096349; hg19: chr12-111082836;