rs149430216

Variant names:

• chr12-123686991-C-G
• rs149430216
• NM_024809.5:c.720C>G

Your query was ambiguous. Multiple possible variants found:

• chr12-123686991-C-G
• chr12-123686991-C-A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_024809.5(TCTN2):​c.720C>G​(p.Pro240Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00489 in 1,614,160 control chromosomes in the GnomAD database, including 31 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 0.0028 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0051 (27 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:5
• Conservation: PhyloP100: -1.02
• Publications: 5 publications found

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 Gene-Disease associations (from GenCC):

• Joubert syndrome 24

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P, Ambry Genetics
• Meckel syndrome, type 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia
• Joubert syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• Meckel syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 12-123686991-C-G is Benign according to our data. Variant chr12-123686991-C-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198261.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00278 (423/152268) while in subpopulation NFE AF = 0.00482 (328/68040). AF 95% confidence interval is 0.00439. There are 4 homozygotes in GnomAd4. There are 180 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024809.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.720C>G	p.Pro240Pro	synonymous	Exon 6 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.717C>G	p.Pro239Pro	synonymous	Exon 6 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.720C>G	p.Pro240Pro	synonymous	Exon 6 of 17	NP_001397918.1	A0A7P0T8X4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.720C>G	p.Pro240Pro	synonymous	Exon 6 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.717C>G	p.Pro239Pro	synonymous	Exon 6 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.720C>G	p.Pro240Pro	synonymous	Exon 6 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.00279 AC: 424 AN: 152150 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00197

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00483

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00262 AC: 658 AN: 251484 AF XY: 0.00247

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.00243

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00470

Gnomad OTH exome AF: 0.00342

GnomAD4 exome AF: 0.00511 AC: 7477 AN: 1461892 Hom.: 27 Cov.: 33 AF XY: 0.00489 AC XY: 3555 AN XY: 727248

African (AFR) AF: 0.00137 AC: 46 AN: 33480

American (AMR) AF: 0.00244 AC: 109 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.000337 AC: 18 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.00631 AC: 7021 AN: 1112010

Other (OTH) AF: 0.00432 AC: 261 AN: 60396

GnomAD4 genome AF: 0.00278 AC: 423 AN: 152268 Hom.: 4 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74448

African (AFR) AF: 0.00130 AC: 54 AN: 41554

American (AMR) AF: 0.00196 AC: 30 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.0000943 AC: 1 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00482 AC: 328 AN: 68040

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00269 Hom.: 0

Bravo AF: 0.00308

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00502

EpiControl AF: 0.00545

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
-	-	2	not specified (2)
-	1	-	Joubert syndrome 24 (1)
-	1	-	Meckel syndrome, type 8 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.58
DANN	Benign	0.59
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

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

Other links and lift over

dbSNP: rs149430216; hg19: chr12-124171538;