rs79251326

Variant names:

• chr12-123686870-G-A
• rs79251326
• NM_024809.5:c.599G>A

Your query was ambiguous. Multiple possible variants found:

• chr12-123686870-G-A
• chr12-123686870-G-T

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1 BP4_Strong BP6 BS1 BS2

The NM_024809.5(TCTN2):​c.599G>A​(p.Arg200Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0119 in 1,614,156 control chromosomes in the GnomAD database, including 161 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R200W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0096 (14 hom., cov: 32)
  • Exomes 𝑓: 0.012 (147 hom.)
• Consequence: TCTN2 NM_024809.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: -0.648
• Publications: 13 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 -11 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_024809.5
• BP4: Computational evidence support a benign effect (MetaRNN=0.003967464).
• BP6: Variant 12-123686870-G-A is Benign according to our data. Variant chr12-123686870-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 126288.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00957 (1457/152274) while in subpopulation AMR AF = 0.0142 (217/15282). AF 95% confidence interval is 0.0129. There are 14 homozygotes in GnomAd4. There are 692 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN2	NM_024809.5	MANE Select	c.599G>A	p.Arg200Gln	missense	Exon 6 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.596G>A	p.Arg199Gln	missense	Exon 6 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.599G>A	p.Arg200Gln	missense	Exon 6 of 17	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.599G>A	p.Arg200Gln	missense	Exon 6 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.596G>A	p.Arg199Gln	missense	Exon 6 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.599G>A	p.Arg200Gln	missense	Exon 6 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.00958 AC: 1457 AN: 152156 Hom.: 14 Cov.: 32

Gnomad AFR AF: 0.00210

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0167

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00228

Gnomad FIN AF: 0.0122

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0137

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.00947 AC: 2382 AN: 251492 AF XY: 0.00933

Gnomad AFR exome AF: 0.00172

Gnomad AMR exome AF: 0.0111

Gnomad ASJ exome AF: 0.0154

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0130

Gnomad NFE exome AF: 0.0124

Gnomad OTH exome AF: 0.00912

GnomAD4 exome AF: 0.0121 AC: 17745 AN: 1461882 Hom.: 147 Cov.: 33 AF XY: 0.0119 AC XY: 8654 AN XY: 727240

African (AFR) AF: 0.00209 AC: 70 AN: 33480

American (AMR) AF: 0.0120 AC: 537 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0160 AC: 419 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00246 AC: 212 AN: 86256

European-Finnish (FIN) AF: 0.0136 AC: 729 AN: 53420

Middle Eastern (MID) AF: 0.00520 AC: 30 AN: 5768

European-Non Finnish (NFE) AF: 0.0136 AC: 15075 AN: 1112004

Other (OTH) AF: 0.0111 AC: 673 AN: 60396

GnomAD4 genome AF: 0.00957 AC: 1457 AN: 152274 Hom.: 14 Cov.: 32 AF XY: 0.00930 AC XY: 692 AN XY: 74448

African (AFR) AF: 0.00209 AC: 87 AN: 41552

American (AMR) AF: 0.0142 AC: 217 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0167 AC: 58 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.00248 AC: 12 AN: 4830

European-Finnish (FIN) AF: 0.0122 AC: 129 AN: 10608

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0137 AC: 930 AN: 68034

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0114 Hom.: 44

Bravo AF: 0.00910

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0132 AC: 51

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00895 AC: 1087

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0140

EpiControl AF: 0.0128

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Meckel syndrome, type 8 (3)
-	-	3	not specified (3)
-	-	1	Joubert syndrome 24 (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	0.041
DANN	Benign	0.59
DEOGEN2	Benign	0.19	T
Eigen	Benign	-2.3
Eigen_PC	Benign	-2.4
FATHMM_MKL	Benign	0.0099	N
LIST_S2	Benign	0.21	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.90	N
PhyloP100		-0.65
PrimateAI	Benign	0.24	T
PROVEAN	Benign	0.010	N
REVEL	Benign	0.23
Sift	Benign	0.63	T
Sift4G	Benign	0.58	T
Polyphen		0.0020	B
Vest4		0.12
MVP		0.46
MPC		0.16
ClinPred		0.00073	T
GERP RS		-9.5
Varity_R		0.020
gMVP		0.22
Mutation Taster		=100/0	polymorphism

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: rs79251326; hg19: chr12-124171417;