12-123697201-G-C

Variant names:

• chr12-123697201-G-C
• rs111574617
• NM_024809.5:c.1505+3G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_024809.5(TCTN2):​c.1505+3G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000722 in 1,600,364 control chromosomes in the GnomAD database, including 6 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00042 (3 hom.)
• Consequence: TCTN2 NM_024809.5 splice_region, intron
• Scores: Splicing: ADA: 0.06464
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.02
• 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, 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 12-123697201-G-C is Benign according to our data. Variant chr12-123697201-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 215939.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00357 (544/152300) while in subpopulation AFR AF = 0.0121 (503/41560). AF 95% confidence interval is 0.0112. There are 3 homozygotes in GnomAd4. There are 259 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.1505+3G>C		splice_region intron	N/A	NP_079085.2
	TCTN2	NM_001143850.3		c.1502+3G>C		splice_region intron	N/A	NP_001137322.1
	TCTN2	NM_001410989.1		c.1370+3G>C		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.1505+3G>C		splice_region intron	N/A	ENSP00000304941.5
	TCTN2	ENST00000426174.6	TSL:2	c.1502+3G>C		splice_region intron	N/A	ENSP00000395171.2
	TCTN2	ENST00000679504.1		c.1502+3G>C		splice_region intron	N/A	ENSP00000505006.1

Frequencies

GnomAD3 genomes AF: 0.00357 AC: 544 AN: 152182 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.0121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000982

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.000959 AC: 241 AN: 251408 AF XY: 0.000787

Gnomad AFR exome AF: 0.0119

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000704

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000423 AC: 612 AN: 1448064 Hom.: 3 Cov.: 27 AF XY: 0.000395 AC XY: 285 AN XY: 721486

African (AFR) AF: 0.0115 AC: 381 AN: 33178

American (AMR) AF: 0.000559 AC: 25 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 44 AN: 26036

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53394

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5738

European-Non Finnish (NFE) AF: 0.0000518 AC: 57 AN: 1099504

Other (OTH) AF: 0.00152 AC: 91 AN: 59956

GnomAD4 genome AF: 0.00357 AC: 544 AN: 152300 Hom.: 3 Cov.: 33 AF XY: 0.00348 AC XY: 259 AN XY: 74466

African (AFR) AF: 0.0121 AC: 503 AN: 41560

American (AMR) AF: 0.000981 AC: 15 AN: 15290

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68032

Other (OTH) AF: 0.00426 AC: 9 AN: 2112

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00369

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	16
DANN	Benign	0.87
PhyloP100		1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.065
dbscSNV1_RF	Benign	0.38
SpliceAI score (max)		0.040		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: rs111574617; hg19: chr12-124181748;