rs12307716

Variant names:

• chr12-110628757-T-A
• rs12307716
• NM_001082538.3:c.473-10T>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001082538.3(TCTN1):​c.473-10T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00658 in 1,586,524 control chromosomes in the GnomAD database, including 290 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (130 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (160 hom.)
• Consequence: TCTN1 NM_001082538.3 intron
• Scores: Splicing: ADA: 0.5244
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.63
• Publications: 1 publications found

Genes affected

TCTN1 (HGNC:26113): (tectonic family member 1) This gene encodes a member of a family of secreted and transmembrane proteins. The orthologous gene in mouse functions downstream of smoothened and rab23 to modulate hedgehog signal transduction. This protein is a component of the tectonic-like complex, which forms a barrier between the ciliary axoneme and the basal body. A mutation in this gene was found in a family with Joubert syndrome-13. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2016]

HVCN1 (HGNC:28240): (hydrogen voltage gated channel 1) This gene encodes a voltage-gated protein channel protein expressed more highly in certain cells of the immune system. Phagocytic cells produce superoxide anions which require this channel protein, and in B cells this same process facilitates antibody production. This same channel protein, however, can also regulate functions in other cells including spermatozoa. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 12-110628757-T-A is Benign according to our data. Variant chr12-110628757-T-A is described in ClinVar as Benign. ClinVar VariationId is 160098.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0775 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001082538.3. 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
	TCTN1	NM_001082538.3	MANE Select	c.473-10T>A		intron	N/A	NP_001076007.1	Q2MV58-2
	TCTN1	NM_001082537.3		c.473-10T>A		intron	N/A	NP_001076006.1	Q2MV58-1
	TCTN1	NM_024549.6		c.473-10T>A		intron	N/A	NP_078825.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN1	ENST00000397659.9	TSL:1 MANE Select	c.473-10T>A		intron	N/A	ENSP00000380779.4	Q2MV58-2
	TCTN1	ENST00000551590.5	TSL:1	c.473-10T>A		intron	N/A	ENSP00000448735.1	Q2MV58-1
	TCTN1	ENST00000397655.7	TSL:1	c.473-10T>A		intron	N/A	ENSP00000380775.3	Q2MV58-3

Frequencies

GnomAD3 genomes AF: 0.0245 AC: 3734 AN: 152162 Hom.: 130 Cov.: 32

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0128

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0116

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00188

Gnomad OTH AF: 0.0177

GnomAD2 exomes AF: 0.00869 AC: 2117 AN: 243572 AF XY: 0.00766

Gnomad AFR exome AF: 0.0827

Gnomad AMR exome AF: 0.00578

Gnomad ASJ exome AF: 0.00372

Gnomad EAS exome AF: 0.000281

Gnomad FIN exome AF: 0.000206

Gnomad NFE exome AF: 0.00191

Gnomad OTH exome AF: 0.00604

GnomAD4 exome AF: 0.00466 AC: 6690 AN: 1434244 Hom.: 160 Cov.: 29 AF XY: 0.00473 AC XY: 3384 AN XY: 715104

African (AFR) AF: 0.0862 AC: 2836 AN: 32886

American (AMR) AF: 0.00647 AC: 288 AN: 44492

Ashkenazi Jewish (ASJ) AF: 0.00320 AC: 83 AN: 25958

East Asian (EAS) AF: 0.000177 AC: 7 AN: 39454

South Asian (SAS) AF: 0.0128 AC: 1091 AN: 85472

European-Finnish (FIN) AF: 0.000298 AC: 15 AN: 50336

Middle Eastern (MID) AF: 0.0114 AC: 63 AN: 5536

European-Non Finnish (NFE) AF: 0.00165 AC: 1795 AN: 1090582

Other (OTH) AF: 0.00860 AC: 512 AN: 59528

GnomAD4 genome AF: 0.0246 AC: 3745 AN: 152280 Hom.: 130 Cov.: 32 AF XY: 0.0237 AC XY: 1763 AN XY: 74476

African (AFR) AF: 0.0798 AC: 3315 AN: 41546

American (AMR) AF: 0.0128 AC: 196 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00288 AC: 10 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.0114 AC: 55 AN: 4830

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10612

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00188 AC: 128 AN: 68014

Other (OTH) AF: 0.0175 AC: 37 AN: 2112

Alfa AF: 0.0130 Hom.: 9

Bravo AF: 0.0284

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not specified (3)
-	-	1	Joubert syndrome 13 (1)
-	-	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	-0.34
CADD	Benign	6.3
DANN	Benign	0.83
PhyloP100		2.6
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.52
dbscSNV1_RF	Benign	0.61
SpliceAI score (max)		0.13		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: rs12307716; hg19: chr12-111066562; COSMIC: COSV66541414; COSMIC: COSV66541414;