rs141768405

Variant names:

• chr12-123671239-G-A
• rs141768405
• NM_024809.5:c.-2G>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.-2G>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 0.000445 in 1,612,594 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0021 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00027 (2 hom.)
• Consequence: TCTN2 NM_024809.5 5_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.147

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 (BayesDel_noAF=-0.73).
• BP6: Variant 12-123671239-G-A is Benign according to our data. Variant chr12-123671239-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193458.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00208 (317/152314) while in subpopulation AFR AF= 0.00688 (286/41580). AF 95% confidence interval is 0.00622. There are 0 homozygotes in gnomad4. There are 160 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.-2G>A		5_prime_UTR_variant	Exon 1 of 18	ENST00000303372.7	NP_079085.2
TCTN2	NM_001143850.3	c.-2G>A		5_prime_UTR_variant	Exon 1 of 18		NP_001137322.1
TCTN2	NM_001410989.1	c.-2G>A		5_prime_UTR_variant	Exon 1 of 17		NP_001397918.1
TCTN2	XM_017019974.2	c.-2G>A		5_prime_UTR_variant	Exon 1 of 17		XP_016875463.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372	c.-2G>A		5_prime_UTR_variant	Exon 1 of 18	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.00210 AC: 319 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00695

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

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: 0.00287

GnomAD3 exomes AF: 0.000531 AC: 131 AN: 246858 Hom.: 0 AF XY: 0.000470 AC XY: 63 AN XY: 134002

Gnomad AFR exome AF: 0.00590

Gnomad AMR exome AF: 0.000437

Gnomad ASJ exome AF: 0.00120

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000628

Gnomad OTH exome AF: 0.000663

GnomAD4 exome AF: 0.000274 AC: 400 AN: 1460280 Hom.: 2 Cov.: 32 AF XY: 0.000268 AC XY: 195 AN XY: 726410

Gnomad4 AFR exome AF: 0.00651

Gnomad4 AMR exome AF: 0.000381

Gnomad4 ASJ exome AF: 0.00172

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000465

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000495

Gnomad4 OTH exome AF: 0.000862

GnomAD4 genome AF: 0.00208 AC: 317 AN: 152314 Hom.: 0 Cov.: 32 AF XY: 0.00215 AC XY: 160 AN XY: 74478

Gnomad4 AFR AF: 0.00688

Gnomad4 AMR AF: 0.000523

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: 0.00284

Alfa AF: 0.00108 Hom.: 0

Bravo AF: 0.00204

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 30, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 08, 2022	See Variant Classification Assertion Criteria. -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 30, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	14
DANN	Benign	0.82
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.16		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: rs141768405; hg19: chr12-124155786;