chr12-123688159-A-G

Variant names:

• chr12-123688159-A-G
• rs73418153
• NM_024809.5:c.873A>G

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.873A>G​(p.Ala291Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0253 in 1,610,976 control chromosomes in the GnomAD database, including 1,189 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.055 (450 hom., cov: 32)
  • Exomes 𝑓: 0.022 (739 hom.)
• Consequence: TCTN2 NM_024809.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -3.58
• Publications: 7 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 12-123688159-A-G is Benign according to our data. Variant chr12-123688159-A-G is described in ClinVar as Benign. ClinVar VariationId is 126292.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.58 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.132 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.873A>G	p.Ala291Ala	synonymous	Exon 7 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.870A>G	p.Ala290Ala	synonymous	Exon 7 of 18	NP_001137322.1
	TCTN2	NM_001410989.1		c.873A>G	p.Ala291Ala	synonymous	Exon 7 of 17	NP_001397918.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	ENST00000303372.7	TSL:1 MANE Select	c.873A>G	p.Ala291Ala	synonymous	Exon 7 of 18	ENSP00000304941.5
	TCTN2	ENST00000426174.6	TSL:2	c.870A>G	p.Ala290Ala	synonymous	Exon 7 of 18	ENSP00000395171.2
	TCTN2	ENST00000679504.1		c.870A>G	p.Ala290Ala	synonymous	Exon 7 of 18	ENSP00000505006.1

Frequencies

GnomAD3 genomes AF: 0.0547 AC: 8313 AN: 151964 Hom.: 452 Cov.: 32

Gnomad AFR AF: 0.135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0747

Gnomad ASJ AF: 0.0225

Gnomad EAS AF: 0.00693

Gnomad SAS AF: 0.0342

Gnomad FIN AF: 0.00663

Gnomad MID AF: 0.0287

Gnomad NFE AF: 0.0171

Gnomad OTH AF: 0.0402

GnomAD2 exomes AF: 0.0297 AC: 7469 AN: 251070 AF XY: 0.0280

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.0492

Gnomad ASJ exome AF: 0.0221

Gnomad EAS exome AF: 0.00696

Gnomad FIN exome AF: 0.00809

Gnomad NFE exome AF: 0.0158

Gnomad OTH exome AF: 0.0228

GnomAD4 exome AF: 0.0222 AC: 32434 AN: 1458902 Hom.: 739 Cov.: 35 AF XY: 0.0224 AC XY: 16262 AN XY: 725838

African (AFR) AF: 0.132 AC: 4378 AN: 33104

American (AMR) AF: 0.0532 AC: 2374 AN: 44630

Ashkenazi Jewish (ASJ) AF: 0.0226 AC: 589 AN: 26102

East Asian (EAS) AF: 0.00439 AC: 174 AN: 39658

South Asian (SAS) AF: 0.0414 AC: 3561 AN: 86038

European-Finnish (FIN) AF: 0.00862 AC: 460 AN: 53356

Middle Eastern (MID) AF: 0.0314 AC: 181 AN: 5758

European-Non Finnish (NFE) AF: 0.0172 AC: 19056 AN: 1109968

Other (OTH) AF: 0.0276 AC: 1661 AN: 60288

GnomAD4 genome AF: 0.0548 AC: 8330 AN: 152074 Hom.: 450 Cov.: 32 AF XY: 0.0541 AC XY: 4025 AN XY: 74338

African (AFR) AF: 0.135 AC: 5585 AN: 41472

American (AMR) AF: 0.0746 AC: 1139 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0225 AC: 78 AN: 3466

East Asian (EAS) AF: 0.00695 AC: 36 AN: 5182

South Asian (SAS) AF: 0.0345 AC: 166 AN: 4816

European-Finnish (FIN) AF: 0.00663 AC: 70 AN: 10564

Middle Eastern (MID) AF: 0.0308 AC: 9 AN: 292

European-Non Finnish (NFE) AF: 0.0171 AC: 1163 AN: 67998

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

Alfa AF: 0.0318 Hom.: 133

Bravo AF: 0.0616

Asia WGS AF: 0.0320 AC: 112 AN: 3478

EpiCase AF: 0.0189

EpiControl AF: 0.0175

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	-0.79
CADD	Benign	0.020
DANN	Benign	0.55
PhyloP100		-3.6
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: rs73418153; hg19: chr12-124172706;