rs112158562

Positions:

• chr12-123707660-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The ENST00000303372.7(TCTN2):​c.2041T>C​(p.Leu681=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0168 in 1,614,186 control chromosomes in the GnomAD database, including 317 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 32)
  • Exomes 𝑓: 0.017 (303 hom.)
• Consequence: TCTN2 ENST00000303372.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.59

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 12-123707660-T-C is Benign according to our data. Variant chr12-123707660-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 126286.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-123707660-T-C is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-1.59 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.0111 (1687/152328) while in subpopulation SAS AF= 0.0308 (149/4832). AF 95% confidence interval is 0.0268. There are 14 homozygotes in gnomad4. There are 833 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.2041T>C	p.Leu681=	synonymous_variant	18/18	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.2041T>C	p.Leu681=	synonymous_variant	18/18	1	NM_024809.5	ENSP00000304941	P4
	ENST00000538837.1	n.263A>G		non_coding_transcript_exon_variant	2/2	3

Frequencies

GnomAD3 genomes AF: 0.0111 AC: 1684 AN: 152210 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00275

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00996

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.00668

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0165

Gnomad OTH AF: 0.00766

GnomAD3 exomes AF: 0.0143 AC: 3566 AN: 249054 Hom.: 50 AF XY: 0.0163 AC XY: 2196 AN XY: 134822

Gnomad AFR exome AF: 0.00314

Gnomad AMR exome AF: 0.00543

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0372

Gnomad FIN exome AF: 0.00813

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0136

GnomAD4 exome AF: 0.0174 AC: 25390 AN: 1461858 Hom.: 303 Cov.: 31 AF XY: 0.0181 AC XY: 13165 AN XY: 727222

Gnomad4 AFR exome AF: 0.00254

Gnomad4 AMR exome AF: 0.00606

Gnomad4 ASJ exome AF: 0.0158

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0387

Gnomad4 FIN exome AF: 0.00863

Gnomad4 NFE exome AF: 0.0177

Gnomad4 OTH exome AF: 0.0158

GnomAD4 genome AF: 0.0111 AC: 1687 AN: 152328 Hom.: 14 Cov.: 32 AF XY: 0.0112 AC XY: 833 AN XY: 74496

Gnomad4 AFR AF: 0.00277

Gnomad4 AMR AF: 0.00994

Gnomad4 ASJ AF: 0.0153

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0308

Gnomad4 FIN AF: 0.00668

Gnomad4 NFE AF: 0.0165

Gnomad4 OTH AF: 0.00758

Alfa AF: 0.0137 Hom.: 12

Bravo AF: 0.00971

Asia WGS AF: 0.0170 AC: 58 AN: 3478

EpiCase AF: 0.0184

EpiControl AF: 0.0167

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	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. -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Sep 06, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Joubert syndrome 24 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Meckel syndrome, type 8 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Cutis laxa, recessive Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.077
DANN	Benign	0.55

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: rs112158562; hg19: chr12-124192207;