chr12-123699783-C-G

Position:

• chr12-123699783-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024809.5(TCTN2):​c.1585C>G​(p.Leu529Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000718 in 1,614,114 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: TCTN2 NM_024809.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.931

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]

TCTN2 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0047388077).
• BP6: Variant 12-123699783-C-G is Benign according to our data. Variant chr12-123699783-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 215940.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 = 0.00355 (540/152282) while in subpopulation AFR AF= 0.012 (498/41552). AF 95% confidence interval is 0.0111. There are 2 homozygotes in gnomad4. There are 257 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN2	NM_024809.5	c.1585C>G	p.Leu529Val	missense_variant	14/18	ENST00000303372.7	NP_079085.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN2	ENST00000303372.7	c.1585C>G	p.Leu529Val	missense_variant	14/18	1	NM_024809.5	ENSP00000304941.5

Frequencies

GnomAD3 genomes AF: 0.00355 AC: 540 AN: 152164 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0120

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

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: 251378 Hom.: 1 AF XY: 0.000788 AC XY: 107 AN XY: 135872

Gnomad AFR exome AF: 0.0120

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: 619 AN: 1461832 Hom.: 3 Cov.: 31 AF XY: 0.000396 AC XY: 288 AN XY: 727210

Gnomad4 AFR exome AF: 0.0116

Gnomad4 AMR exome AF: 0.000559

Gnomad4 ASJ exome AF: 0.00168

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000513

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00355 AC: 540 AN: 152282 Hom.: 2 Cov.: 32 AF XY: 0.00345 AC XY: 257 AN XY: 74458

Gnomad4 AFR AF: 0.0120

Gnomad4 AMR AF: 0.00105

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: 0.000463 Hom.: 0

Bravo AF: 0.00369

ESP6500AA AF: 0.0102 AC: 45

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00122 AC: 148

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:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 13, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 18, 2018	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	.;T
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.65	T;T
MetaRNN	Benign	0.0047	T;T
MetaSVM	Benign	-0.68	T
MutationAssessor	Uncertain	2.8	.;M
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.25
Sift	Benign	0.096	T;T
Sift4G	Uncertain	0.048	D;D
Polyphen		0.36	.;B
Vest4		0.15
MVP		0.57
MPC		0.20
ClinPred		0.038	T
GERP RS		5.0
Varity_R		0.15
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs113301547; hg19: chr12-124184330; COSMIC: COSV105146759;