chr12-123694981-C-G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_024809.5(TCTN2):​c.1234+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

TCTN2
NM_024809.5 splice_region, intron

Scores

2
Splicing: ADA: 0.00005413
2

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: -0.669

Publications

0 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

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -5 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.8).
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000112 (17/152190) while in subpopulation AMR AF = 0.000981 (15/15284). AF 95% confidence interval is 0.000604. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TCTN2NM_024809.5 linkc.1234+5C>G splice_region_variant, intron_variant Intron 10 of 17 ENST00000303372.7 NP_079085.2 Q96GX1-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TCTN2ENST00000303372.7 linkc.1234+5C>G splice_region_variant, intron_variant Intron 10 of 17 1 NM_024809.5 ENSP00000304941.5 Q96GX1-1

Frequencies

GnomAD3 genomes
AF:
0.000112
AC:
17
AN:
152072
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000983
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD2 exomes
AF:
0.00000400
AC:
1
AN:
249952
AF XY:
0.00000737
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000479
AC:
7
AN:
1460902
Hom.:
0
Cov.:
33
AF XY:
0.00000275
AC XY:
2
AN XY:
726752
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33458
American (AMR)
AF:
0.0000671
AC:
3
AN:
44702
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26104
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39662
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86214
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53364
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5568
European-Non Finnish (NFE)
AF:
9.00e-7
AC:
1
AN:
1111506
Other (OTH)
AF:
0.0000497
AC:
3
AN:
60324
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.482
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000112
AC:
17
AN:
152190
Hom.:
0
Cov.:
33
AF XY:
0.000108
AC XY:
8
AN XY:
74398
show subpopulations
African (AFR)
AF:
0.0000481
AC:
2
AN:
41538
American (AMR)
AF:
0.000981
AC:
15
AN:
15284
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4812
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10576
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68004
Other (OTH)
AF:
0.00
AC:
0
AN:
2112
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.484
Heterozygous variant carriers
0
2
3
5
6
8
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.0000282
Hom.:
0
Bravo
AF:
0.000257

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Dec 12, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Meckel-Gruber syndrome;C0431399:Joubert syndrome Uncertain:1
Oct 13, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change falls in intron 10 of the TCTN2 gene. It does not directly change the encoded amino acid sequence of the TCTN2 protein. It affects a nucleotide within the consensus splice site. This variant is present in population databases (rs201382614, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with TCTN2-related conditions. ClinVar contains an entry for this variant (Variation ID: 408315). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.80
CADD
Benign
11
DANN
Benign
0.59
PhyloP100
-0.67

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000054
dbscSNV1_RF
Benign
0.014
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

Other links and lift over

dbSNP: rs201382614; hg19: chr12-124179528; API