TCTN2 p.Gly373Arg

Variant names:

• chr12-123694859-G-C
• NM_024809.5:c.1117G>C
• TCTN2 p.Gly373Arg

Your query was ambiguous. Multiple possible variants found:

• chr12-123694859-G-C
• chr12-123694859-G-A
• chr12-123694859-GGA-CGT
• chr12-123694859-GGA-CGC
• chr12-123694859-GGA-CGG
• chr12-123694859-GGA-AGG

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PS1_Moderate PM2

The NM_024809.5(TCTN2):​c.1117G>C​(p.Gly373Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TCTN2 NM_024809.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.808
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• Meckel syndrome, type 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• Joubert syndrome

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

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PS1: Transcript NM_024809.5 (TCTN2) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage

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.1117G>C	p.Gly373Arg	missense	Exon 10 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.1114G>C	p.Gly372Arg	missense	Exon 10 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.1100-361G>C		intron	N/A	NP_001397918.1	A0A7P0T8X4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.1117G>C	p.Gly373Arg	missense	Exon 10 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.1114G>C	p.Gly372Arg	missense	Exon 10 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.1117G>C	p.Gly373Arg	missense	Exon 10 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	15
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.67	D
Eigen	Benign	-0.34
Eigen_PC	Benign	-0.53
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.81
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.48
Sift	Benign	0.22	T
Sift4G	Benign	0.30	T
Varity_R		0.084
gMVP		0.57
Mutation Taster		=32/68	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -17

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr12-124179406;