dbSNP rs76843552: TCTN1:c.220+12G>C (chr12-110614414-G-C) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 8P and 16B. PVS1BP6_Very_StrongBS1BS2

The NM_001173975.3(TCTN1):c.3G>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0091 in 1,585,846 control chromosomes in the GnomAD database, including 73 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0071 ( 1 hom., cov: 31)

Exomes 𝑓: 0.0093 ( 72 hom. )

Consequence

TCTN1
NM_001173975.3 start_lost

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.350

Publications

6 publications found

Variant links:

Genes affected

TCTN1 (HGNC:26113): (tectonic family member 1) This gene encodes a member of a family of secreted and transmembrane proteins. The orthologous gene in mouse functions downstream of smoothened and rab23 to modulate hedgehog signal transduction. This protein is a component of the tectonic-like complex, which forms a barrier between the ciliary axoneme and the basal body. A mutation in this gene was found in a family with Joubert syndrome-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

TCTN1 Gene-Disease associations (from GenCC):

Joubert syndrome 13
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia
Joubert syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
Meckel syndrome
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

TCTN1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

PVS1

Start lost variant, next in-frame start position is after 7 pathogenic variants. Next in-frame start position is after 123 codons. Genomic position: 110628829. Lost 0.230 part of the original CDS.

BP6

Variant 12-110614414-G-C is Benign according to our data. Variant chr12-110614414-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 160096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00706 (1076/152356) while in subpopulation NFE AF = 0.00941 (640/68030). AF 95% confidence interval is 0.0088. There are 1 homozygotes in GnomAd4. There are 521 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 72 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173975.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
TCTN1	NM_001082538.3	MANE Select	c.220+12G>C		intron	N/A	NP_001076007.1	Q2MV58-2
TCTN1	NM_001173975.3		c.3G>C	p.Met1?	start_lost	Exon 1 of 15	NP_001167446.1	Q2MV58-4
TCTN1	NM_001319682.3		c.3G>C	p.Met1?	start_lost	Exon 1 of 4	NP_001306611.1	Q05BR9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
TCTN1	ENST00000397659.9	TSL:1 MANE Select	c.220+12G>C	intron	N/A	ENSP00000380779.4	Q2MV58-2
TCTN1	ENST00000551590.5	TSL:1	c.220+12G>C	intron	N/A	ENSP00000448735.1	Q2MV58-1
TCTN1	ENST00000397655.7	TSL:1	c.220+12G>C	intron	N/A	ENSP00000380775.3	Q2MV58-3

Frequencies

GnomAD3 genomes

AF:

0.00707

AC:

1076

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00203

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00897

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.0169

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00941

Gnomad OTH

AF:

0.00430

GnomAD2 exomes

AF:

0.00800

AC:

1545

AN:

193076

AF XY:

0.00803

show subpopulations

Gnomad AFR exome

AF:

0.00202

Gnomad AMR exome

AF:

0.00551

Gnomad ASJ exome

AF:

0.00204

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0198

Gnomad NFE exome

AF:

0.0102

Gnomad OTH exome

AF:

0.0110

GnomAD4 exome

AF:

0.00932

AC:

13357

AN:

1433490

Hom.:

Cov.:

AF XY:

0.00924

AC XY:

6566

AN XY:

710472

show subpopulations

African (AFR)

AF:

0.00248

AC:

AN:

33026

American (AMR)

AF:

0.00569

AC:

231

AN:

40566

Ashkenazi Jewish (ASJ)

AF:

0.00141

AC:

AN:

25472

East Asian (EAS)

AF:

0.00

AC:

AN:

38662

South Asian (SAS)

AF:

0.00552

AC:

456

AN:

82580

European-Finnish (FIN)

AF:

0.0184

AC:

923

AN:

50216

Middle Eastern (MID)

AF:

0.00296

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.0102

AC:

11222

AN:

1097962

Other (OTH)

AF:

0.00658

AC:

390

AN:

59264

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

873

1746

2618

3491

4364

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

432

864

1296

1728

2160

<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:

0.00706

AC:

1076

AN:

152356

Hom.:

Cov.:

AF XY:

0.00699

AC XY:

521

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.00204

AC:

AN:

41586

American (AMR)

AF:

0.00889

AC:

136

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00144

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5192

South Asian (SAS)

AF:

0.00414

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.0169

AC:

180

AN:

10630

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00941

AC:

640

AN:

68030

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

123

185

246

308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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

Alfa

AF:

0.00160

Hom.:

Bravo

AF:

0.00626

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

not specified (3)

Joubert syndrome 13 (1)

Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_noAF

Benign

-0.82

CADD

Benign

6.4

(source)

DANN

Benign

0.95

PhyloP100

-0.35

PromoterAI

0.13

Neutral

(source)

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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