NM_024809.5:c.1234+5C>G

Variant names:

• chr12-123694981-C-G
• rs201382614
• NM_024809.5:c.1234+5C>G

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_024809.5(TCTN2):​c.1234+5C>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,092 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: TCTN2 NM_024809.5 splice_region, intron
• Scores: Splicing: ADA: 0.00005413
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: -0.669
• Publications: 0 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000112 (17/152190) while in subpopulation AMR AF = 0.000981 (15/15284). AF 95% confidence interval is 0.000604. There are 0 homozygotes in GnomAd4. There are 8 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1234+5C>G		splice_region intron	N/A	NP_079085.2
	TCTN2	NM_001143850.3		c.1231+5C>G		splice_region intron	N/A	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.1100-239C>G		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.1234+5C>G		splice_region intron	N/A	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.1231+5C>G		splice_region intron	N/A	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.1234+5C>G		splice_region intron	N/A	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 152072 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000983

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00000400 AC: 1 AN: 249952 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1460902 Hom.: 0 Cov.: 33 AF XY: 0.00000275 AC XY: 2 AN XY: 726752

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.0000671 AC: 3 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00 AC: 0 AN: 86214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5568

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111506

Other (OTH) AF: 0.0000497 AC: 3 AN: 60324

GnomAD4 genome AF: 0.000112 AC: 17 AN: 152190 Hom.: 0 Cov.: 33 AF XY: 0.000108 AC XY: 8 AN XY: 74398

African (AFR) AF: 0.0000481 AC: 2 AN: 41538

American (AMR) AF: 0.000981 AC: 15 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.000257

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	11
DANN	Benign	0.59
PhyloP100		-0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000054
dbscSNV1_RF	Benign	0.014
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

Other links and lift over

dbSNP: rs201382614; hg19: chr12-124179528;