rs111574617

Positions:

• chr12-123697201-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_024809.5(TCTN2):​c.1505+3G>C variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,600,364 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: TCTN2 NM_024809.5 splice_donor_region, intron
• Scores: Splicing: ADA: 0.06464
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.02

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-123697201-G-C is Benign according to our data. Variant chr12-123697201-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 215939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00357 (544/152300) while in subpopulation AFR AF= 0.0121 (503/41560). AF 95% confidence interval is 0.0112. There are 3 homozygotes in gnomad4. There are 259 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TCTN2	NM_024809.5	c.1505+3G>C		splice_donor_region_variant, intron_variant		ENST00000303372.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TCTN2	ENST00000303372.7	c.1505+3G>C		splice_donor_region_variant, intron_variant		1	NM_024809.5	P4

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 544 AN: 152182 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.000959 AC: 241 AN: 251408 Hom.: 1 AF XY: 0.000787 AC XY: 107 AN XY: 135878

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000423 AC: 612 AN: 1448064 Hom.: 3 Cov.: 27 AF XY: 0.000395 AC XY: 285 AN XY: 721486

Gnomad4 AFR exome AF: 0.0115

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00169

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000518

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152300 Hom.: 3 Cov.: 33 AF XY: 0.00348 AC XY: 259 AN XY: 74466

Gnomad4 AFR AF: 0.0121

Gnomad4 AMR AF: 0.000981

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00369

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2022

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Apr 18, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.87

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.065
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.040		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: rs111574617; hg19: chr12-124181748;