dbSNP rs113301547: TCTN2:p.Leu529Val (chr12-123699783-C-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_024809.5(TCTN2):c.1585C>G(p.Leu529Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,614,114 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0035 ( 2 hom., cov: 32)

Exomes 𝑓: 0.00042 ( 3 hom. )

Consequence

TCTN2
NM_024809.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.931

Publications

4 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, 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

TCTN2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0047388077).

BP6

Variant 12-123699783-C-G is Benign according to our data. Variant chr12-123699783-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215940.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00355 (540/152282) while in subpopulation AFR AF = 0.012 (498/41552). AF 95% confidence interval is 0.0111. There are 2 homozygotes in GnomAd4. There are 257 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 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
TCTN2	NM_024809.5	MANE Select	c.1585C>G	p.Leu529Val	missense	Exon 14 of 18	NP_079085.2
TCTN2	NM_001143850.3		c.1582C>G	p.Leu528Val	missense	Exon 14 of 18	NP_001137322.1
TCTN2	NM_001410989.1		c.1450C>G	p.Leu484Val	missense	Exon 13 of 17	NP_001397918.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.1585C>G	p.Leu529Val	missense	Exon 14 of 18	ENSP00000304941.5
TCTN2	ENST00000426174.6	TSL:2	c.1582C>G	p.Leu528Val	missense	Exon 14 of 18	ENSP00000395171.2
TCTN2	ENST00000965363.1		c.1507C>G	p.Leu503Val	missense	Exon 13 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes

AF:

0.00355

AC:

540

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0120

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00105

Gnomad ASJ

AF:

0.00230

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00431

GnomAD2 exomes

AF:

0.000959

AC:

241

AN:

251378

AF XY:

0.000788

show subpopulations

Gnomad AFR exome

AF:

0.0120

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000704

Gnomad OTH exome

AF:

0.000815

GnomAD4 exome

AF:

0.000423

AC:

619

AN:

1461832

Hom.:

Cov.:

AF XY:

0.000396

AC XY:

288

AN XY:

727210

show subpopulations

African (AFR)

AF:

0.0116

AC:

387

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00168

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.0000580

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00156

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0000513

AC:

AN:

1111966

Other (OTH)

AF:

0.00152

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<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:

0.00355

AC:

540

AN:

152282

Hom.:

Cov.:

AF XY:

0.00345

AC XY:

257

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.0120

AC:

498

AN:

41552

American (AMR)

AF:

0.00105

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00230

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5184

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68034

Other (OTH)

AF:

0.00426

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

117

146

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.000463

Hom.:

Bravo

AF:

0.00369

ESP6500AA

AF:

0.0102

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00122

AC:

148

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000119

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (2)

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

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.083

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.15

Eigen

Benign

-0.33

Eigen_PC

Benign

-0.31

FATHMM_MKL

Benign

0.19

LIST_S2

Benign

0.65

MetaRNN

Benign

0.0047

MetaSVM

Benign

-0.68

MutationAssessor

Uncertain

2.8

PhyloP100

0.93

PrimateAI

Benign

0.32

PROVEAN

Benign

-1.3

REVEL

Benign

0.25

Sift

Benign

0.096

Sift4G

Uncertain

0.048

Polyphen

0.36

Vest4

0.15

MVP

0.57

MPC

0.20

ClinPred

0.038

GERP RS

5.0

Varity_R

0.15

gMVP

0.53

Mutation Taster

=96/4

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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