NM_001082538.3:c.1234A>G

Variant names:

• chr12-110642292-A-G
• rs75714509
• NM_001082538.3:c.1234A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001082538.3(TCTN1):​c.1234A>G​(p.Ile412Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00908 in 1,614,188 control chromosomes in the GnomAD database, including 73 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I412T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0071 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0093 (72 hom.)
• Consequence: TCTN1 NM_001082538.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0910
• Publications: 10 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0039714277).
• BP6: Variant 12-110642292-A-G is Benign according to our data. Variant chr12-110642292-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 93533.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0071 (1082/152306) while in subpopulation NFE AF = 0.00944 (642/68026). AF 95% confidence interval is 0.00883. There are 1 homozygotes in GnomAd4. There are 526 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 72 AR gene

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.1234A>G	p.Ile412Val	missense	Exon 11 of 15	NP_001076007.1	Q2MV58-2
	TCTN1	NM_001082537.3		c.1234A>G	p.Ile412Val	missense	Exon 11 of 15	NP_001076006.1	Q2MV58-1
	TCTN1	NM_024549.6		c.1192A>G	p.Ile398Val	missense	Exon 11 of 15	NP_078825.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TCTN1	ENST00000397659.9	TSL:1 MANE Select	c.1234A>G	p.Ile412Val	missense	Exon 11 of 15	ENSP00000380779.4	Q2MV58-2
	TCTN1	ENST00000551590.5	TSL:1	c.1234A>G	p.Ile412Val	missense	Exon 11 of 15	ENSP00000448735.1	Q2MV58-1
	TCTN1	ENST00000397655.7	TSL:1	c.1192A>G	p.Ile398Val	missense	Exon 11 of 15	ENSP00000380775.3	Q2MV58-3

Frequencies

GnomAD3 genomes AF: 0.00711 AC: 1082 AN: 152188 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00208

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00896

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0170

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00944

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00759 AC: 1894 AN: 249562 AF XY: 0.00768

Gnomad AFR exome AF: 0.00161

Gnomad AMR exome AF: 0.00518

Gnomad ASJ exome AF: 0.00199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0192

Gnomad NFE exome AF: 0.00931

Gnomad OTH exome AF: 0.0102

GnomAD4 exome AF: 0.00929 AC: 13577 AN: 1461882 Hom.: 72 Cov.: 31 AF XY: 0.00920 AC XY: 6693 AN XY: 727238

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.00552 AC: 247 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00145 AC: 38 AN: 26136

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

South Asian (SAS) AF: 0.00546 AC: 471 AN: 86256

European-Finnish (FIN) AF: 0.0184 AC: 984 AN: 53418

Middle Eastern (MID) AF: 0.00295 AC: 17 AN: 5768

European-Non Finnish (NFE) AF: 0.0102 AC: 11330 AN: 1112006

Other (OTH) AF: 0.00674 AC: 407 AN: 60396

GnomAD4 genome AF: 0.00710 AC: 1082 AN: 152306 Hom.: 1 Cov.: 32 AF XY: 0.00706 AC XY: 526 AN XY: 74478

African (AFR) AF: 0.00209 AC: 87 AN: 41566

American (AMR) AF: 0.00889 AC: 136 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4822

European-Finnish (FIN) AF: 0.0170 AC: 180 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00944 AC: 642 AN: 68026

Other (OTH) AF: 0.00473 AC: 10 AN: 2116

Alfa AF: 0.00825 Hom.: 27

Bravo AF: 0.00627

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.0101 AC: 39

ESP6500AA AF: 0.00186 AC: 7

ESP6500EA AF: 0.00864 AC: 71

ExAC AF: 0.00738 AC: 892

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.00812

EpiControl AF: 0.00901

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	not provided (3)
-	-	1	Joubert syndrome 13 (1)
-	-	1	Meckel-Gruber syndrome;C0431399:Joubert syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	1.9
DANN	Benign	0.74
DEOGEN2	Benign	0.073	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.033	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0040	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.74	N
PhyloP100		-0.091
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.073
Sift	Benign	0.39	T
Sift4G	Benign	0.25	T
Polyphen		0.0010	B
Vest4		0.072
MVP		0.13
MPC		0.17
ClinPred		0.00056	T
GERP RS		-3.8
Varity_R		0.024
gMVP		0.38
Mutation Taster		=98/2	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: rs75714509; hg19: chr12-111080097; COSMIC: COSV105305215; COSMIC: COSV105305215;