rs863225221

Variant names:

• chr12-123695276-G-T
• rs863225221
• NM_024809.5:c.1291G>T

Variant summary

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

The NM_024809.5(TCTN2):​c.1291G>T​(p.Glu431*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Synonymous variant affecting the same amino acid position (i.e. E431E) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCTN2 NM_024809.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -1.22
• Publications: 0 publications found

Genes affected

TCTN2 (HGNC:25774): (tectonic family member 2) This gene encodes a type I membrane protein that belongs to the tectonic family. Studies in mice suggest that this protein may be involved in hedgehog signaling, and essential for ciliogenesis. Mutations in this gene are associated with Meckel syndrome type 8. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

TCTN2 Gene-Disease associations (from GenCC):

• Joubert syndrome 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

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 12-123695276-G-T is Pathogenic according to our data. Variant chr12-123695276-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 217699.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024809.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.1291G>T	p.Glu431*	stop_gained	Exon 11 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.1288G>T	p.Glu430*	stop_gained	Exon 11 of 18	NP_001137322.1
	TCTN2	NM_001410989.1		c.1156G>T	p.Glu386*	stop_gained	Exon 10 of 17	NP_001397918.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.1291G>T	p.Glu431*	stop_gained	Exon 11 of 18	ENSP00000304941.5
	TCTN2	ENST00000426174.6	TSL:2	c.1288G>T	p.Glu430*	stop_gained	Exon 11 of 18	ENSP00000395171.2
	TCTN2	ENST00000679504.1		c.1288G>T	p.Glu430*	stop_gained	Exon 11 of 18	ENSP00000505006.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.62	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	34
DANN	Benign	0.96
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.80
FATHMM_MKL	Benign	0.025	N
PhyloP100		-1.2
Vest4		0.23
GERP RS		-7.6
Mutation Taster		=3/197	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.85		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.85		Position offset: 21

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

Other links and lift over

dbSNP: rs863225221; hg19: chr12-124179823;