chr12-123694870-T-C

Variant names:

• chr12-123694870-T-C
• rs7966867
• NM_024809.5:c.1128T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_024809.5(TCTN2):​c.1128T>C​(p.Pro376Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.457 in 1,611,480 control chromosomes in the GnomAD database, including 177,967 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.53 (24168 hom., cov: 32)
  • Exomes 𝑓: 0.45 (153799 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.320
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 12-123694870-T-C is Benign according to our data. Variant chr12-123694870-T-C is described in ClinVar as Benign. ClinVar VariationId is 126283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.32 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.815 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.1128T>C	p.Pro376Pro	synonymous	Exon 10 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.1125T>C	p.Pro375Pro	synonymous	Exon 10 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.1100-350T>C		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.1128T>C	p.Pro376Pro	synonymous	Exon 10 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.1125T>C	p.Pro375Pro	synonymous	Exon 10 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.1128T>C	p.Pro376Pro	synonymous	Exon 10 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.530 AC: 80470 AN: 151964 Hom.: 24113 Cov.: 32

Gnomad AFR AF: 0.822

Gnomad AMI AF: 0.552

Gnomad AMR AF: 0.399

Gnomad ASJ AF: 0.405

Gnomad EAS AF: 0.150

Gnomad SAS AF: 0.464

Gnomad FIN AF: 0.347

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.492

GnomAD2 exomes AF: 0.424 AC: 106367 AN: 251142 AF XY: 0.427

Gnomad AFR exome AF: 0.834

Gnomad AMR exome AF: 0.277

Gnomad ASJ exome AF: 0.400

Gnomad EAS exome AF: 0.153

Gnomad FIN exome AF: 0.360

Gnomad NFE exome AF: 0.450

Gnomad OTH exome AF: 0.430

GnomAD4 exome AF: 0.449 AC: 655228 AN: 1459398 Hom.: 153799 Cov.: 34 AF XY: 0.450 AC XY: 326406 AN XY: 725976

African (AFR) AF: 0.841 AC: 28119 AN: 33426

American (AMR) AF: 0.292 AC: 13029 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 10315 AN: 26068

East Asian (EAS) AF: 0.121 AC: 4806 AN: 39656

South Asian (SAS) AF: 0.492 AC: 42388 AN: 86218

European-Finnish (FIN) AF: 0.356 AC: 18971 AN: 53306

Middle Eastern (MID) AF: 0.469 AC: 2702 AN: 5756

European-Non Finnish (NFE) AF: 0.457 AC: 507534 AN: 1110020

Other (OTH) AF: 0.454 AC: 27364 AN: 60266

GnomAD4 genome AF: 0.530 AC: 80579 AN: 152082 Hom.: 24168 Cov.: 32 AF XY: 0.521 AC XY: 38724 AN XY: 74350

African (AFR) AF: 0.822 AC: 34127 AN: 41514

American (AMR) AF: 0.399 AC: 6093 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.405 AC: 1406 AN: 3470

East Asian (EAS) AF: 0.149 AC: 774 AN: 5184

South Asian (SAS) AF: 0.463 AC: 2232 AN: 4822

European-Finnish (FIN) AF: 0.347 AC: 3658 AN: 10546

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30593 AN: 67966

Other (OTH) AF: 0.495 AC: 1045 AN: 2112

Alfa AF: 0.472 Hom.: 35393

Bravo AF: 0.541

Asia WGS AF: 0.357 AC: 1245 AN: 3478

EpiCase AF: 0.453

EpiControl AF: 0.453

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Meckel syndrome, type 8 (4)
-	-	3	not specified (3)
-	-	2	Joubert syndrome 24 (2)
-	-	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	-0.95
CADD	Benign	5.6
DANN	Benign	0.55
PhyloP100		0.32
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: rs7966867; hg19: chr12-124179417; COSMIC: COSV57631977; COSMIC: COSV57631977;