chr12-123671186-C-A

Position:

• chr12-123671186-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024809.5(TCTN2):​c.-55C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0498 in 1,539,316 control chromosomes in the GnomAD database, including 2,134 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (134 hom., cov: 32)
  • Exomes 𝑓: 0.051 (2000 hom.)
• Consequence: TCTN2 NM_024809.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.489

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 12-123671186-C-A is Benign according to our data. Variant chr12-123671186-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 307542.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0561 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.-55C>A		5_prime_UTR_variant	1/18	ENST00000303372.7	NP_079085.2
TCTN2	NM_001143850.3	c.-55C>A		5_prime_UTR_variant	1/18		NP_001137322.1
TCTN2	NM_001410989.1	c.-55C>A		5_prime_UTR_variant	1/17		NP_001397918.1
TCTN2	XM_017019974.2	c.-55C>A		5_prime_UTR_variant	1/17		XP_016875463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.-55C>A		5_prime_UTR_variant	1/18	1	NM_024809.5	ENSP00000304941	P4

Frequencies

GnomAD3 genomes AF: 0.0374 AC: 5693 AN: 152140 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.00871

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0249

Gnomad ASJ AF: 0.0432

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0418

Gnomad FIN AF: 0.0459

Gnomad MID AF: 0.0506

Gnomad NFE AF: 0.0576

Gnomad OTH AF: 0.0450

GnomAD4 exome AF: 0.0512 AC: 71005 AN: 1387058 Hom.: 2000 Cov.: 23 AF XY: 0.0512 AC XY: 35373 AN XY: 690360

Gnomad4 AFR exome AF: 0.00731

Gnomad4 AMR exome AF: 0.0224

Gnomad4 ASJ exome AF: 0.0363

Gnomad4 EAS exome AF: 0.000106

Gnomad4 SAS exome AF: 0.0452

Gnomad4 FIN exome AF: 0.0476

Gnomad4 NFE exome AF: 0.0564

Gnomad4 OTH exome AF: 0.0498

GnomAD4 genome AF: 0.0374 AC: 5693 AN: 152258 Hom.: 134 Cov.: 32 AF XY: 0.0370 AC XY: 2754 AN XY: 74444

Gnomad4 AFR AF: 0.00869

Gnomad4 AMR AF: 0.0249

Gnomad4 ASJ AF: 0.0432

Gnomad4 EAS AF: 0.000387

Gnomad4 SAS AF: 0.0421

Gnomad4 FIN AF: 0.0459

Gnomad4 NFE AF: 0.0576

Gnomad4 OTH AF: 0.0440

Alfa AF: 0.0371 Hom.: 32

Bravo AF: 0.0334

Asia WGS AF: 0.0230 AC: 81 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	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. -

Joubert syndrome 24 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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 13, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	9.0
DANN	Benign	0.40
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

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: rs78846567; hg19: chr12-124155733; COSMIC: COSV57632274;