12-123695192-A-G

Variant names:

• chr12-123695192-A-G
• rs12831081
• NM_024809.5:c.1235-28A>G

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.1235-28A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.365 in 1,474,422 control chromosomes in the GnomAD database, including 102,844 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10273 hom., cov: 32)
  • Exomes 𝑓: 0.37 (92571 hom.)
• Consequence: TCTN2 NM_024809.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.58
• Publications: 10 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=-0.85).
• BP6: Variant 12-123695192-A-G is Benign according to our data. Variant chr12-123695192-A-G is described in ClinVar as Benign. ClinVar VariationId is 126284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.406 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.1235-28A>G		intron_variant	Intron 10 of 17	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.1235-28A>G		intron_variant	Intron 10 of 17	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.359 AC: 54508 AN: 151896 Hom.: 10266 Cov.: 32

Gnomad AFR AF: 0.411

Gnomad AMI AF: 0.514

Gnomad AMR AF: 0.269

Gnomad ASJ AF: 0.323

Gnomad EAS AF: 0.0564

Gnomad SAS AF: 0.311

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.383

Gnomad OTH AF: 0.352

GnomAD2 exomes AF: 0.318 AC: 79285 AN: 249592 AF XY: 0.325

Gnomad AFR exome AF: 0.418

Gnomad AMR exome AF: 0.195

Gnomad ASJ exome AF: 0.319

Gnomad EAS exome AF: 0.0554

Gnomad FIN exome AF: 0.305

Gnomad NFE exome AF: 0.382

Gnomad OTH exome AF: 0.345

GnomAD4 exome AF: 0.366 AC: 483773 AN: 1322406 Hom.: 92571 Cov.: 20 AF XY: 0.365 AC XY: 243076 AN XY: 665794

African (AFR) AF: 0.424 AC: 12967 AN: 30588

American (AMR) AF: 0.202 AC: 9000 AN: 44494

Ashkenazi Jewish (ASJ) AF: 0.317 AC: 7976 AN: 25134

East Asian (EAS) AF: 0.0471 AC: 1836 AN: 38952

South Asian (SAS) AF: 0.333 AC: 27777 AN: 83350

European-Finnish (FIN) AF: 0.303 AC: 16080 AN: 53112

Middle Eastern (MID) AF: 0.367 AC: 1897 AN: 5162

European-Non Finnish (NFE) AF: 0.392 AC: 386629 AN: 985996

Other (OTH) AF: 0.353 AC: 19611 AN: 55618

GnomAD4 genome AF: 0.359 AC: 54548 AN: 152016 Hom.: 10273 Cov.: 32 AF XY: 0.353 AC XY: 26257 AN XY: 74304

African (AFR) AF: 0.412 AC: 17054 AN: 41438

American (AMR) AF: 0.269 AC: 4103 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.323 AC: 1121 AN: 3468

East Asian (EAS) AF: 0.0563 AC: 292 AN: 5186

South Asian (SAS) AF: 0.310 AC: 1494 AN: 4814

European-Finnish (FIN) AF: 0.296 AC: 3127 AN: 10576

Middle Eastern (MID) AF: 0.378 AC: 111 AN: 294

European-Non Finnish (NFE) AF: 0.383 AC: 26042 AN: 67960

Other (OTH) AF: 0.347 AC: 735 AN: 2116

Alfa AF: 0.370 Hom.: 3483

Bravo AF: 0.359

Asia WGS AF: 0.184 AC: 644 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	-0.85
CADD	Benign	0.0090
DANN	Benign	0.85
PhyloP100		-1.6
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: rs12831081; hg19: chr12-124179739;