12-123688096-C-T

Variant names:

• chr12-123688096-C-T
• rs144567556
• NM_024809.5:c.810C>T

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.810C>T​(p.Asp270Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00626 in 1,613,986 control chromosomes in the GnomAD database, including 46 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 0.0039 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0065 (42 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: -2.65
• Publications: 7 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=-0.75).
• BP6: Variant 12-123688096-C-T is Benign according to our data. Variant chr12-123688096-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 198593.
• BP7: Synonymous conserved (PhyloP=-2.65 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00393 (598/152238) while in subpopulation NFE AF = 0.0062 (422/68010). AF 95% confidence interval is 0.00572. There are 4 homozygotes in GnomAd4. There are 272 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.810C>T	p.Asp270Asp	synonymous	Exon 7 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.807C>T	p.Asp269Asp	synonymous	Exon 7 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.810C>T	p.Asp270Asp	synonymous	Exon 7 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.810C>T	p.Asp270Asp	synonymous	Exon 7 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.807C>T	p.Asp269Asp	synonymous	Exon 7 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.810C>T	p.Asp270Asp	synonymous	Exon 7 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.00394 AC: 599 AN: 152120 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00328

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00255

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00622

Gnomad OTH AF: 0.00670

GnomAD2 exomes AF: 0.00376 AC: 946 AN: 251486 AF XY: 0.00358

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00179

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00245

Gnomad NFE exome AF: 0.00610

Gnomad OTH exome AF: 0.00537

GnomAD4 exome AF: 0.00651 AC: 9513 AN: 1461748 Hom.: 42 Cov.: 35 AF XY: 0.00624 AC XY: 4537 AN XY: 727182

African (AFR) AF: 0.00137 AC: 46 AN: 33476

American (AMR) AF: 0.00329 AC: 147 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00184 AC: 48 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39690

South Asian (SAS) AF: 0.000243 AC: 21 AN: 86256

European-Finnish (FIN) AF: 0.00234 AC: 125 AN: 53402

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5768

European-Non Finnish (NFE) AF: 0.00788 AC: 8765 AN: 1111912

Other (OTH) AF: 0.00586 AC: 354 AN: 60388

GnomAD4 genome AF: 0.00393 AC: 598 AN: 152238 Hom.: 4 Cov.: 32 AF XY: 0.00365 AC XY: 272 AN XY: 74442

African (AFR) AF: 0.00181 AC: 75 AN: 41538

American (AMR) AF: 0.00327 AC: 50 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00230 AC: 8 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4826

European-Finnish (FIN) AF: 0.00255 AC: 27 AN: 10602

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

European-Non Finnish (NFE) AF: 0.00620 AC: 422 AN: 68010

Other (OTH) AF: 0.00663 AC: 14 AN: 2112

Alfa AF: 0.00383 Hom.: 0

Bravo AF: 0.00410

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00589

EpiControl AF: 0.00676

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	2	not provided (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	-0.75
CADD	Benign	0.51
DANN	Benign	0.33
PhyloP100		-2.7
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: rs144567556; hg19: chr12-124172643; COSMIC: COSV57632936;