12-110628757-TAAA-T

Variant names:

• chr12-110628757-TAAA-T
• rs10577377
• NM_001082538.3:c.473-6_473-4delAAA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001082538.3(TCTN1):​c.473-6_473-4delAAA variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00374 in 1,586,552 control chromosomes in the GnomAD database, including 339 homozygotes. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (22 hom., cov: 32)
  • Exomes 𝑓: 0.0035 (317 hom.)
• Consequence: TCTN1 NM_001082538.3 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 2.67
• Publications: 2 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 -16 ACMG points.

• BP6: Variant 12-110628757-TAAA-T is Benign according to our data. Variant chr12-110628757-TAAA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93534.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAdExome4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.105 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.473-6_473-4delAAA		splice_region intron	N/A	NP_001076007.1	Q2MV58-2
	TCTN1	NM_001082537.3		c.473-6_473-4delAAA		splice_region intron	N/A	NP_001076006.1	Q2MV58-1
	TCTN1	NM_024549.6		c.473-6_473-4delAAA		splice_region 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.473-9_473-7delAAA		splice_region intron	N/A	ENSP00000380779.4	Q2MV58-2
	TCTN1	ENST00000551590.5	TSL:1	c.473-9_473-7delAAA		splice_region intron	N/A	ENSP00000448735.1	Q2MV58-1
	TCTN1	ENST00000397655.7	TSL:1	c.473-9_473-7delAAA		splice_region intron	N/A	ENSP00000380775.3	Q2MV58-3

Frequencies

GnomAD3 genomes AF: 0.00548 AC: 834 AN: 152168 Hom.: 22 Cov.: 32

Gnomad AFR AF: 0.00167

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0486

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00574

GnomAD2 exomes AF: 0.0172 AC: 4196 AN: 243572 AF XY: 0.0128

Gnomad AFR exome AF: 0.00151

Gnomad AMR exome AF: 0.120

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000618

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000722

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.00355 AC: 5085 AN: 1434266 Hom.: 317 AF XY: 0.00293 AC XY: 2097 AN XY: 715120

African (AFR) AF: 0.000790 AC: 26 AN: 32906

American (AMR) AF: 0.108 AC: 4801 AN: 44474

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25958

East Asian (EAS) AF: 0.00223 AC: 88 AN: 39452

South Asian (SAS) AF: 0.000117 AC: 10 AN: 85478

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50336

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5538

European-Non Finnish (NFE) AF: 0.0000358 AC: 39 AN: 1090594

Other (OTH) AF: 0.00203 AC: 121 AN: 59530

GnomAD4 genome AF: 0.00553 AC: 842 AN: 152286 Hom.: 22 Cov.: 32 AF XY: 0.00636 AC XY: 474 AN XY: 74478

African (AFR) AF: 0.00166 AC: 69 AN: 41554

American (AMR) AF: 0.0490 AC: 750 AN: 15300

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

East Asian (EAS) AF: 0.000964 AC: 5 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10612

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.00568 AC: 12 AN: 2112

Alfa AF: 0.000875 Hom.: 0

Bravo AF: 0.0108

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	not specified (2)
-	-	1	Joubert syndrome (1)
-	-	1	Meckel-Gruber syndrome;C5979921:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.7
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: rs10577377; hg19: chr12-111066562;