12-123699822-C-T

Variant names:

• chr12-123699822-C-T
• rs117614122
• NM_024809.5:c.1612+12C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_024809.5(TCTN2):​c.1612+12C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0176 in 1,608,546 control chromosomes in the GnomAD database, including 307 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 0.014 (14 hom., cov: 32)
  • Exomes 𝑓: 0.018 (293 hom.)
• Consequence: TCTN2 NM_024809.5 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.621
• Publications: 1 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BP6: Variant 12-123699822-C-T is Benign according to our data. Variant chr12-123699822-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 261787.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0136 (2077/152230) while in subpopulation NFE AF = 0.0212 (1444/68020). AF 95% confidence interval is 0.0203. There are 14 homozygotes in GnomAd4. There are 965 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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.1612+12C>T		intron	N/A	NP_079085.2
	TCTN2	NM_001143850.3		c.1609+12C>T		intron	N/A	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.1477+12C>T		intron	N/A	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.1612+12C>T		intron	N/A	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.1609+12C>T		intron	N/A	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.1534+12C>T		intron	N/A	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.0137 AC: 2077 AN: 152112 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00408

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00963

Gnomad ASJ AF: 0.0216

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00497

Gnomad FIN AF: 0.0184

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0212

Gnomad OTH AF: 0.00959

GnomAD2 exomes AF: 0.0141 AC: 3545 AN: 250922 AF XY: 0.0143

Gnomad AFR exome AF: 0.00371

Gnomad AMR exome AF: 0.00790

Gnomad ASJ exome AF: 0.0182

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.0164

Gnomad NFE exome AF: 0.0214

Gnomad OTH exome AF: 0.0166

GnomAD4 exome AF: 0.0181 AC: 26301 AN: 1456316 Hom.: 293 Cov.: 29 AF XY: 0.0178 AC XY: 12921 AN XY: 724822

African (AFR) AF: 0.00288 AC: 96 AN: 33362

American (AMR) AF: 0.00827 AC: 370 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0185 AC: 484 AN: 26100

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39684

South Asian (SAS) AF: 0.00506 AC: 436 AN: 86148

European-Finnish (FIN) AF: 0.0151 AC: 808 AN: 53336

Middle Eastern (MID) AF: 0.0125 AC: 72 AN: 5758

European-Non Finnish (NFE) AF: 0.0208 AC: 23018 AN: 1107028

Other (OTH) AF: 0.0169 AC: 1015 AN: 60180

GnomAD4 genome AF: 0.0136 AC: 2077 AN: 152230 Hom.: 14 Cov.: 32 AF XY: 0.0130 AC XY: 965 AN XY: 74444

African (AFR) AF: 0.00407 AC: 169 AN: 41548

American (AMR) AF: 0.00962 AC: 147 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.0216 AC: 75 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00498 AC: 24 AN: 4822

European-Finnish (FIN) AF: 0.0184 AC: 195 AN: 10586

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0212 AC: 1444 AN: 68020

Other (OTH) AF: 0.00949 AC: 20 AN: 2108

Alfa AF: 0.0176 Hom.: 45

Bravo AF: 0.0125

Asia WGS AF: 0.00433 AC: 15 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	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	-0.90
CADD	Benign	0.39
DANN	Benign	0.61
PhyloP100		-0.62
Mutation Taster		=100/0	polymorphism (auto)

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: rs117614122; hg19: chr12-124184369;