12-123671503-C-T

Variant names:

• chr12-123671503-C-T
• rs73416299
• NM_024809.5:c.83-4C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_024809.5(TCTN2):​c.83-4C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,613,974 control chromosomes in the GnomAD database, including 1,194 homozygotes. 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (449 hom., cov: 32)
  • Exomes 𝑓: 0.023 (745 hom.)
• Consequence: TCTN2 NM_024809.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004354
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.106
• Publications: 6 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, G2P, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 12-123671503-C-T is Benign according to our data. Variant chr12-123671503-C-T is described in ClinVar as Benign. ClinVar VariationId is 126291.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.83-4C>T		splice_region intron	N/A	NP_079085.2
	TCTN2	NM_001143850.3		c.83-4C>T		splice_region intron	N/A	NP_001137322.1
	TCTN2	NM_001410989.1		c.83-4C>T		splice_region intron	N/A	NP_001397918.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.83-4C>T		splice_region intron	N/A	ENSP00000304941.5
	TCTN2	ENST00000426174.6	TSL:2	c.83-4C>T		splice_region intron	N/A	ENSP00000395171.2
	TCTN2	ENST00000679504.1		c.83-4C>T		splice_region intron	N/A	ENSP00000505006.1

Frequencies

GnomAD3 genomes AF: 0.0546 AC: 8311 AN: 152130 Hom.: 451 Cov.: 32

Gnomad AFR AF: 0.134

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.0231

Gnomad EAS AF: 0.00674

Gnomad SAS AF: 0.0344

Gnomad FIN AF: 0.00659

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0305 AC: 7661 AN: 251372 AF XY: 0.0288

Gnomad AFR exome AF: 0.134

Gnomad AMR exome AF: 0.0500

Gnomad ASJ exome AF: 0.0225

Gnomad EAS exome AF: 0.00701

Gnomad FIN exome AF: 0.00809

Gnomad NFE exome AF: 0.0162

Gnomad OTH exome AF: 0.0231

GnomAD4 exome AF: 0.0230 AC: 33637 AN: 1461726 Hom.: 745 Cov.: 32 AF XY: 0.0232 AC XY: 16838 AN XY: 727186

African (AFR) AF: 0.136 AC: 4549 AN: 33476

American (AMR) AF: 0.0540 AC: 2413 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0230 AC: 601 AN: 26136

East Asian (EAS) AF: 0.00443 AC: 176 AN: 39700

South Asian (SAS) AF: 0.0425 AC: 3663 AN: 86252

European-Finnish (FIN) AF: 0.00861 AC: 460 AN: 53404

Middle Eastern (MID) AF: 0.0324 AC: 187 AN: 5768

European-Non Finnish (NFE) AF: 0.0179 AC: 19903 AN: 1111870

Other (OTH) AF: 0.0279 AC: 1685 AN: 60396

GnomAD4 genome AF: 0.0547 AC: 8327 AN: 152248 Hom.: 449 Cov.: 32 AF XY: 0.0540 AC XY: 4022 AN XY: 74434

African (AFR) AF: 0.134 AC: 5577 AN: 41518

American (AMR) AF: 0.0748 AC: 1144 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0231 AC: 80 AN: 3468

East Asian (EAS) AF: 0.00675 AC: 35 AN: 5184

South Asian (SAS) AF: 0.0346 AC: 167 AN: 4826

European-Finnish (FIN) AF: 0.00659 AC: 70 AN: 10624

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0171 AC: 1161 AN: 68024

Other (OTH) AF: 0.0398 AC: 84 AN: 2112

Alfa AF: 0.0335 Hom.: 153

Bravo AF: 0.0616

Asia WGS AF: 0.0310 AC: 111 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0174

ClinVar

ClinVar submissions as Germline

Significance: 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;C0431399:Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.91
PhyloP100		0.11
PromoterAI		0.066	Neutral
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000044
dbscSNV1_RF	Benign	0.012
SpliceAI score (max)		0.030		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: rs73416299; hg19: chr12-124156050;