rs138897437

Variant names:

• chr12-123686925-C-T
• rs138897437
• NM_024809.5:c.654C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-123686925-C-T
• chr12-123686925-C-G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_024809.5(TCTN2):​c.654C>T​(p.Leu218Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00193 in 1,614,204 control chromosomes in the GnomAD database, including 74 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (21 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (53 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.352
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 12-123686925-C-T is Benign according to our data. Variant chr12-123686925-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 126289.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.352 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00548 (835/152312) while in subpopulation AMR AF = 0.0472 (721/15272). AF 95% confidence interval is 0.0444. There are 21 homozygotes in GnomAd4. There are 514 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 21 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.654C>T	p.Leu218Leu	synonymous	Exon 6 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.651C>T	p.Leu217Leu	synonymous	Exon 6 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.654C>T	p.Leu218Leu	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.654C>T	p.Leu218Leu	synonymous	Exon 6 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.651C>T	p.Leu217Leu	synonymous	Exon 6 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.654C>T	p.Leu218Leu	synonymous	Exon 6 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.00549 AC: 836 AN: 152194 Hom.: 21 Cov.: 32

Gnomad AFR AF: 0.00113

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0473

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00597

Gnomad SAS AF: 0.00186

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00602 AC: 1514 AN: 251490 AF XY: 0.00492

Gnomad AFR exome AF: 0.000861

Gnomad AMR exome AF: 0.0372

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00685

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00505

GnomAD4 exome AF: 0.00156 AC: 2283 AN: 1461892 Hom.: 53 Cov.: 33 AF XY: 0.00148 AC XY: 1075 AN XY: 727246

African (AFR) AF: 0.000657 AC: 22 AN: 33480

American (AMR) AF: 0.0396 AC: 1773 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00433 AC: 172 AN: 39700

South Asian (SAS) AF: 0.00187 AC: 161 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000270 AC: 30 AN: 1112012

Other (OTH) AF: 0.00207 AC: 125 AN: 60396

GnomAD4 genome AF: 0.00548 AC: 835 AN: 152312 Hom.: 21 Cov.: 32 AF XY: 0.00690 AC XY: 514 AN XY: 74480

African (AFR) AF: 0.00113 AC: 47 AN: 41588

American (AMR) AF: 0.0472 AC: 721 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00598 AC: 31 AN: 5182

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68034

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.00221 Hom.: 5

Bravo AF: 0.00854

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	1.3
DANN	Benign	0.63
PhyloP100		0.35
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: rs138897437; hg19: chr12-124171472;