chr12-123687063-G-C

Variant names:

• chr12-123687063-G-C
• rs73418148
• NM_024809.5:c.764+28G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_024809.5(TCTN2):​c.764+28G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0191 in 1,613,730 control chromosomes in the GnomAD database, including 420 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (59 hom., cov: 32)
  • Exomes 𝑓: 0.019 (361 hom.)
• Consequence: TCTN2 NM_024809.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -1.74
• Publications: 4 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=-0.93).
• BP6: Variant 12-123687063-G-C is Benign according to our data. Variant chr12-123687063-G-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 261791.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 = 0.0239 (3635/152278) while in subpopulation AFR AF = 0.0469 (1948/41546). AF 95% confidence interval is 0.0452. There are 59 homozygotes in GnomAd4. There are 1724 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 59 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.764+28G>C		intron	N/A	NP_079085.2
	TCTN2	NM_001143850.3		c.761+28G>C		intron	N/A	NP_001137322.1
	TCTN2	NM_001410989.1		c.764+28G>C		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.764+28G>C		intron	N/A	ENSP00000304941.5
	TCTN2	ENST00000426174.6	TSL:2	c.761+28G>C		intron	N/A	ENSP00000395171.2
	TCTN2	ENST00000679504.1		c.761+28G>C		intron	N/A	ENSP00000505006.1

Frequencies

GnomAD3 genomes AF: 0.0238 AC: 3626 AN: 152160 Hom.: 59 Cov.: 32

Gnomad AFR AF: 0.0469

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0158

Gnomad ASJ AF: 0.0153

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0304

Gnomad FIN AF: 0.00660

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0172

GnomAD2 exomes AF: 0.0176 AC: 4412 AN: 251324 AF XY: 0.0185

Gnomad AFR exome AF: 0.0477

Gnomad AMR exome AF: 0.00728

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00813

Gnomad NFE exome AF: 0.0159

Gnomad OTH exome AF: 0.0153

GnomAD4 exome AF: 0.0187 AC: 27267 AN: 1461452 Hom.: 361 Cov.: 32 AF XY: 0.0192 AC XY: 13965 AN XY: 727036

African (AFR) AF: 0.0473 AC: 1582 AN: 33466

American (AMR) AF: 0.00859 AC: 384 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 412 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39694

South Asian (SAS) AF: 0.0392 AC: 3378 AN: 86248

European-Finnish (FIN) AF: 0.00863 AC: 461 AN: 53410

Middle Eastern (MID) AF: 0.0285 AC: 164 AN: 5762

European-Non Finnish (NFE) AF: 0.0178 AC: 19736 AN: 1111650

Other (OTH) AF: 0.0190 AC: 1148 AN: 60372

GnomAD4 genome AF: 0.0239 AC: 3635 AN: 152278 Hom.: 59 Cov.: 32 AF XY: 0.0232 AC XY: 1724 AN XY: 74458

African (AFR) AF: 0.0469 AC: 1948 AN: 41546

American (AMR) AF: 0.0158 AC: 241 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0153 AC: 53 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5184

South Asian (SAS) AF: 0.0308 AC: 149 AN: 4830

European-Finnish (FIN) AF: 0.00660 AC: 70 AN: 10612

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1129 AN: 68030

Other (OTH) AF: 0.0170 AC: 36 AN: 2112

Alfa AF: 0.00799 Hom.: 0

Bravo AF: 0.0260

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 29, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.052
DANN	Benign	0.46
PhyloP100		-1.7
Mutation Taster		=100/0	polymorphism (auto)

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: rs73418148; hg19: chr12-124171610;