chr12-123706833-T-C

Variant names:

• chr12-123706833-T-C
• rs786204788
• NM_024809.5:c.1877T>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024809.5(TCTN2):​c.1877T>C​(p.Leu626Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. L626L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TCTN2 NM_024809.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.354
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05162725).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.1877T>C	p.Leu626Ser	missense	Exon 16 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.1874T>C	p.Leu625Ser	missense	Exon 16 of 18	NP_001137322.1
	TCTN2	NM_001410989.1		c.1742T>C	p.Leu581Ser	missense	Exon 15 of 17	NP_001397918.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.1877T>C	p.Leu626Ser	missense	Exon 16 of 18	ENSP00000304941.5
	TCTN2	ENST00000426174.6	TSL:2	c.1874T>C	p.Leu625Ser	missense	Exon 16 of 18	ENSP00000395171.2
	TCTN2	ENST00000679504.1		c.1874T>C	p.Leu625Ser	missense	Exon 16 of 18	ENSP00000505006.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251494 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727246

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

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

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	14
DANN	Benign	0.67
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.021	N
LIST_S2	Benign	0.73	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.052	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.35
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.90	N
REVEL	Benign	0.11
Sift	Benign	0.89	T
Sift4G	Benign	0.49	T
Polyphen		0.040	B
Vest4		0.34
MutPred		0.38		Gain of catalytic residue at L630 (P = 8e-04)
MVP		0.46
MPC		0.22
ClinPred		0.98	D
GERP RS		2.5
Varity_R		0.054
gMVP		0.59
Mutation Taster		=91/9	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: rs786204788; hg19: chr12-124191380;