rs7298831

Variant names:

• chr12-123688008-A-T
• rs7298831
• NM_024809.5:c.765-43A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024809.5(TCTN2):​c.765-43A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,608,040 control chromosomes in the GnomAD database, including 129,642 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13872 hom., cov: 31)
  • Exomes 𝑓: 0.39 (115770 hom.)
• Consequence: TCTN2 NM_024809.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.238
• Publications: 13 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 12-123688008-A-T is Benign according to our data. Variant chr12-123688008-A-T is described in ClinVar as [Benign]. Clinvar id is 126290.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.765-43A>T		intron_variant	Intron 6 of 17	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.765-43A>T		intron_variant	Intron 6 of 17	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62812 AN: 151834 Hom.: 13855 Cov.: 31

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.513

Gnomad AMR AF: 0.344

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.0626

Gnomad SAS AF: 0.345

Gnomad FIN AF: 0.302

Gnomad MID AF: 0.415

Gnomad NFE AF: 0.400

Gnomad OTH AF: 0.391

GnomAD2 exomes AF: 0.348 AC: 87439 AN: 251046 AF XY: 0.353

Gnomad AFR exome AF: 0.551

Gnomad AMR exome AF: 0.245

Gnomad ASJ exome AF: 0.342

Gnomad EAS exome AF: 0.0624

Gnomad FIN exome AF: 0.312

Gnomad NFE exome AF: 0.398

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.391 AC: 569068 AN: 1456090 Hom.: 115770 Cov.: 32 AF XY: 0.390 AC XY: 282606 AN XY: 724468

African (AFR) AF: 0.560 AC: 18662 AN: 33324

American (AMR) AF: 0.256 AC: 11422 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.340 AC: 8831 AN: 25980

East Asian (EAS) AF: 0.0515 AC: 2035 AN: 39528

South Asian (SAS) AF: 0.376 AC: 32333 AN: 86050

European-Finnish (FIN) AF: 0.311 AC: 16469 AN: 52916

Middle Eastern (MID) AF: 0.398 AC: 2279 AN: 5726

European-Non Finnish (NFE) AF: 0.410 AC: 454083 AN: 1107880

Other (OTH) AF: 0.382 AC: 22954 AN: 60084

GnomAD4 genome AF: 0.414 AC: 62868 AN: 151950 Hom.: 13872 Cov.: 31 AF XY: 0.408 AC XY: 30274 AN XY: 74272

African (AFR) AF: 0.547 AC: 22634 AN: 41396

American (AMR) AF: 0.344 AC: 5243 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1202 AN: 3468

East Asian (EAS) AF: 0.0625 AC: 323 AN: 5166

South Asian (SAS) AF: 0.344 AC: 1657 AN: 4816

European-Finnish (FIN) AF: 0.302 AC: 3193 AN: 10572

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.400 AC: 27216 AN: 67982

Other (OTH) AF: 0.386 AC: 812 AN: 2104

Alfa AF: 0.402 Hom.: 2295

Bravo AF: 0.420

Asia WGS AF: 0.217 AC: 758 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

-

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.76
DANN	Benign	0.74
PhyloP100		-0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs7298831; hg19: chr12-124172555; COSMIC: COSV57634615;