NM_024809.5:c.-80G>A

Variant names:

• chr12-123671161-G-A
• rs191193522
• NM_024809.5:c.-80G>A

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.-80G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00166 in 1,366,446 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0081 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (17 hom.)
• Consequence: TCTN2 NM_024809.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.128
• Publications: 3 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 12-123671161-G-A is Benign according to our data. Variant chr12-123671161-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 1188149.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 = 0.00814 (1240/152340) while in subpopulation AFR AF = 0.0281 (1170/41590). AF 95% confidence interval is 0.0268. There are 13 homozygotes in GnomAd4. There are 553 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 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.-80G>A		5_prime_UTR	Exon 1 of 18	NP_079085.2
	TCTN2	NM_001143850.3		c.-80G>A		5_prime_UTR	Exon 1 of 18	NP_001137322.1	Q96GX1-2
	TCTN2	NM_001410989.1		c.-80G>A		5_prime_UTR	Exon 1 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.-80G>A		5_prime_UTR	Exon 1 of 18	ENSP00000304941.5	Q96GX1-1
	TCTN2	ENST00000426174.6	TSL:2	c.-80G>A		5_prime_UTR	Exon 1 of 18	ENSP00000395171.2	Q96GX1-2
	TCTN2	ENST00000965363.1		c.-80G>A		5_prime_UTR	Exon 1 of 17	ENSP00000635422.1

Frequencies

GnomAD3 genomes AF: 0.00812 AC: 1236 AN: 152222 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0281

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00366

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00621

GnomAD4 exome AF: 0.000850 AC: 1032 AN: 1214106 Hom.: 17 Cov.: 17 AF XY: 0.000710 AC XY: 432 AN XY: 608686

African (AFR) AF: 0.0294 AC: 828 AN: 28136

American (AMR) AF: 0.00186 AC: 67 AN: 36086

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24184

East Asian (EAS) AF: 0.00 AC: 0 AN: 35180

South Asian (SAS) AF: 0.000183 AC: 14 AN: 76578

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39554

Middle Eastern (MID) AF: 0.000566 AC: 3 AN: 5304

European-Non Finnish (NFE) AF: 0.00000763 AC: 7 AN: 916996

Other (OTH) AF: 0.00217 AC: 113 AN: 52088

GnomAD4 genome AF: 0.00814 AC: 1240 AN: 152340 Hom.: 13 Cov.: 32 AF XY: 0.00742 AC XY: 553 AN XY: 74484

African (AFR) AF: 0.0281 AC: 1170 AN: 41590

American (AMR) AF: 0.00366 AC: 56 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68036

Other (OTH) AF: 0.00615 AC: 13 AN: 2114

Alfa AF: 0.0136 Hom.: 9

Bravo AF: 0.00948

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	3.9
DANN	Benign	0.89
PhyloP100		-0.13
PromoterAI		-0.15	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Mutation Taster		=300/0	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: rs191193522; hg19: chr12-124155708;