NM_024809.5:c.810C>G

Variant names:

• chr12-123688096-C-G
• rs144567556
• NM_024809.5:c.810C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_024809.5(TCTN2):​c.810C>G​(p.Asp270Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,760 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict 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 Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. D270D) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TCTN2 NM_024809.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.65
• 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, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13265142).

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.810C>G	p.Asp270Glu	missense	Exon 7 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.807C>G	p.Asp269Glu	missense	Exon 7 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.810C>G	p.Asp270Glu	missense	Exon 7 of 17	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.810C>G	p.Asp270Glu	missense	Exon 7 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.807C>G	p.Asp269Glu	missense	Exon 7 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.810C>G	p.Asp270Glu	missense	Exon 7 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461760 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727186

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111924

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	0.0020
DANN	Benign	0.37
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.31	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	1.1	L
PhyloP100		-2.7
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.60	N
REVEL	Uncertain	0.31
Sift	Benign	0.80	T
Sift4G	Benign	0.41	T
Polyphen		0.031	B
Vest4		0.088
MutPred		0.63		Gain of catalytic residue at F274 (P = 0.0071)
MVP		0.46
MPC		0.15
ClinPred		0.083	T
GERP RS		-11
Varity_R		0.048
gMVP		0.43
Mutation Taster		=98/2	polymorphism

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

Other links and lift over

dbSNP: rs144567556; hg19: chr12-124172643;