Genetic Variant TCTN2:p.Leu300Leu (chr12-123690539-C-T) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_024809.5(TCTN2):c.898C>T(p.Leu300Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,162 control chromosomes in the GnomAD database, including 319 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 14 hom., cov: 32)

Exomes 𝑓: 0.017 ( 305 hom. )

Consequence

TCTN2
NM_024809.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.0540

Publications

10 publications found

Variant links:

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

TCTN2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.39).

BP6

Variant 12-123690539-C-T is Benign according to our data. Variant chr12-123690539-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.054 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0111 (1688/152318) while in subpopulation SAS AF = 0.0306 (148/4830). AF 95% confidence interval is 0.0266. There are 14 homozygotes in GnomAd4. There are 833 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 14 AR gene

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCTN2	NM_024809.5	MANE Select	c.898C>T	p.Leu300Leu	synonymous	Exon 8 of 18	NP_079085.2
TCTN2	NM_001143850.3		c.895C>T	p.Leu299Leu	synonymous	Exon 8 of 18	NP_001137322.1	Q96GX1-2
TCTN2	NM_001410989.1		c.898C>T	p.Leu300Leu	synonymous	Exon 8 of 17	NP_001397918.1	A0A7P0T8X4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.898C>T	p.Leu300Leu	synonymous	Exon 8 of 18	ENSP00000304941.5	Q96GX1-1
TCTN2	ENST00000426174.6	TSL:2	c.895C>T	p.Leu299Leu	synonymous	Exon 8 of 18	ENSP00000395171.2	Q96GX1-2
TCTN2	ENST00000965363.1		c.898C>T	p.Leu300Leu	synonymous	Exon 8 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes

AF:

0.0111

AC:

1685

AN:

152200

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00277

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00996

Gnomad ASJ

AF:

0.0153

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0302

Gnomad FIN

AF:

0.00669

Gnomad MID

AF:

0.0190

Gnomad NFE

AF:

0.0165

Gnomad OTH

AF:

0.00764

GnomAD2 exomes

AF:

0.0143

AC:

3601

AN:

251478

AF XY:

0.0163

show subpopulations

Gnomad AFR exome

AF:

0.00314

Gnomad AMR exome

AF:

0.00544

Gnomad ASJ exome

AF:

0.0156

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.00813

Gnomad NFE exome

AF:

0.0158

Gnomad OTH exome

AF:

0.0137

GnomAD4 exome

AF:

0.0174

AC:

25398

AN:

1461844

Hom.:

305

Cov.:

AF XY:

0.0181

AC XY:

13181

AN XY:

727228

show subpopulations

African (AFR)

AF:

0.00254

AC:

AN:

33480

American (AMR)

AF:

0.00606

AC:

271

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0158

AC:

412

AN:

26136

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39698

South Asian (SAS)

AF:

0.0389

AC:

3351

AN:

86252

European-Finnish (FIN)

AF:

0.00863

AC:

461

AN:

53416

Middle Eastern (MID)

AF:

0.0272

AC:

157

AN:

5768

European-Non Finnish (NFE)

AF:

0.0177

AC:

19709

AN:

1111976

Other (OTH)

AF:

0.0157

AC:

950

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.466

Heterozygous variant carriers

1415

2830

4244

5659

7074

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

776

1552

2328

3104

3880

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0111

AC:

1688

AN:

152318

Hom.:

Cov.:

AF XY:

0.0112

AC XY:

833

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.00279

AC:

116

AN:

41586

American (AMR)

AF:

0.00994

AC:

152

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.0153

AC:

AN:

3468

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.0306

AC:

148

AN:

4830

European-Finnish (FIN)

AF:

0.00669

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.0204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0165

AC:

1124

AN:

68022

Other (OTH)

AF:

0.00756

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

184

276

368

460

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

104

130

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0140

Hom.:

Bravo

AF:

0.00971

Asia WGS

AF:

0.0170

AC:

AN:

3478

EpiCase

AF:

0.0184

EpiControl

AF:

0.0168

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Joubert syndrome 24 (1)

Meckel syndrome, type 8 (1)

Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.39

CADD

Benign

7.2

(source)

DANN

Benign

0.64

PhyloP100

-0.054

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over