rs797046039

Variant names:

• chr12-110636500-AG-A
• rs797046039
• ENST00000397659.9:c.832delG

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PVS1 PM2 PP3_Moderate PP5_Moderate

The ENST00000397659.9(TCTN1):​c.832delG​(p.Ser278SerfsTer13) variant causes a frameshift change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCTN1 ENST00000397659.9 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.56
• Publications: 1 publications found

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

Our verdict: Pathogenic. The variant received 14 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-110636500-AG-A is Pathogenic according to our data. Variant chr12-110636500-AG-A is described in ClinVar as Pathogenic. ClinVar VariationId is 212386.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.843+1delG		splice_donor_variant, intron_variant	Intron 7 of 14	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.832delG	p.Ser278SerfsTer13	frameshift_variant	Exon 7 of 15	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.832delG	p.Ser278SerfsTer13	frameshift_variant	Exon 7 of 15	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.790delG	p.Ser264SerfsTer13	frameshift_variant	Exon 7 of 15	1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.*465delG		non_coding_transcript_exon_variant	Exon 8 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.*108delG		non_coding_transcript_exon_variant	Exon 8 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*590delG		non_coding_transcript_exon_variant	Exon 7 of 15	2		ENSP00000436673.2
TCTN1	ENST00000397656.8	n.*465delG		3_prime_UTR_variant	Exon 8 of 16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.*108delG		3_prime_UTR_variant	Exon 8 of 16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*590delG		3_prime_UTR_variant	Exon 7 of 15	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 22

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Joubert syndrome 13 Pathogenic:1

Feb 19, 2014

Genetic Services Laboratory, University of Chicago

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.6
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.54		Position offset: 0
DS_DL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs797046039; hg19: chr12-111074305;