rs79251326

chr12-123686870-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024809.5(TCTN2):c.599G>A(p.Arg200Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,156 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (147 hom.)
• Consequence: TCTN2 NM_024809.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.648

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003967464).
• BP6: Variant 12-123686870-G-A is Benign according to our data. Variant chr12-123686870-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 126288.We mark this variant Likely_benign, oryginal submissions are: {Benign=6, Uncertain_significance=1, Likely_benign=2}. Variant chr12-123686870-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00957 (1457/152274) while in subpopulation AMR AF= 0.0142 (217/15282). AF 95% confidence interval is 0.0129. There are 14 homozygotes in gnomad4. There are 692 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN2	NM_024809.5	c.599G>A	p.Arg200Gln	missense_variant	6/18	ENST00000303372.7
TCTN2	NM_001143850.3	c.596G>A	p.Arg199Gln	missense_variant	6/18
TCTN2	NM_001410989.1	c.599G>A	p.Arg200Gln	missense_variant	6/17
TCTN2	XM_017019974.2	c.596G>A	p.Arg199Gln	missense_variant	6/17

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN2	ENST00000303372.7	c.599G>A	p.Arg200Gln	missense_variant	6/18	1	NM_024809.5	P4

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1457 AN: 152156 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.00947 AC: 2382 AN: 251492 Hom.: 19 AF XY: 0.00933 AC XY: 1268 AN XY: 135922

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00229

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0121 AC: 17745 AN: 1461882 Hom.: 147 Cov.: 33 AF XY: 0.0119 AC XY: 8654 AN XY: 727240

Gnomad4 AFR exome AF: 0.00209

Gnomad4 AMR exome AF: 0.0120

Gnomad4 ASJ exome AF: 0.0160

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00246

Gnomad4 FIN exome AF: 0.0136

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.00957 AC: 1457 AN: 152274 Hom.: 14 Cov.: 32 AF XY: 0.00930 AC XY: 692 AN XY: 74448

Gnomad4 AFR AF: 0.00209

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0167

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00248

Gnomad4 FIN AF: 0.0122

Gnomad4 NFE AF: 0.0137

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0120 Hom.: 21

Bravo AF: 0.00910

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00895 AC: 1087

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0128

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Meckel syndrome, type 8 Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	Sep 21, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Jan 19, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jul 20, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 09, 2017	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. -

Meckel-Gruber syndrome;C0431399:Familial aplasia of the vermis Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Joubert syndrome 24 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2024

TCTN2: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
Cadd	Benign	0.041
Dann	Benign	0.59
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.21	T;T
MetaRNN	Benign	0.0040	T;T
MetaSVM	Benign	-0.88	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.010	N;N
REVEL	Benign	0.23
Sift	Benign	0.63	T;T
Sift4G	Benign	0.58	T;T
Polyphen		0.0020	.;B
Vest4		0.12
MVP		0.46
MPC		0.16
ClinPred		0.00073	T
GERP RS		-9.5
Varity_R		0.020
gMVP		0.22

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs79251326; hg19: chr12-124171417;