rs188817098

Variant names:

• chr12-110642349-G-C
• rs188817098
• NM_001082538.3:c.1291G>C

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 0P and 3B. BP4_Moderate BS1_Supporting

The NM_001082538.3(TCTN1):​c.1291G>C​(p.Val431Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,614,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (1 hom.)
• Consequence: TCTN1 NM_001082538.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:1
• Conservation: PhyloP100: 2.27
• Publications: 4 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: Likely_benign. The variant received -3 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.1541287).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.000722 (110/152318) while in subpopulation NFE AF = 0.00129 (88/68032). AF 95% confidence interval is 0.00107. There are 0 homozygotes in GnomAd4. There are 56 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

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.1291G>C	p.Val431Leu	missense	Exon 11 of 15	NP_001076007.1	Q2MV58-2
	TCTN1	NM_001082537.3		c.1291G>C	p.Val431Leu	missense	Exon 11 of 15	NP_001076006.1	Q2MV58-1
	TCTN1	NM_024549.6		c.1249G>C	p.Val417Leu	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.1291G>C	p.Val431Leu	missense	Exon 11 of 15	ENSP00000380779.4	Q2MV58-2
	TCTN1	ENST00000551590.5	TSL:1	c.1291G>C	p.Val431Leu	missense	Exon 11 of 15	ENSP00000448735.1	Q2MV58-1
	TCTN1	ENST00000397655.7	TSL:1	c.1249G>C	p.Val417Leu	missense	Exon 11 of 15	ENSP00000380775.3	Q2MV58-3

Frequencies

GnomAD3 genomes AF: 0.000723 AC: 110 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000392

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00129

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000753 AC: 188 AN: 249574 AF XY: 0.000835

Gnomad AFR exome AF: 0.000129

Gnomad AMR exome AF: 0.000319

Gnomad ASJ exome AF: 0.000199

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00126

Gnomad OTH exome AF: 0.000495

GnomAD4 exome AF: 0.00111 AC: 1618 AN: 1461884 Hom.: 1 Cov.: 31 AF XY: 0.00109 AC XY: 796 AN XY: 727240

African (AFR) AF: 0.000239 AC: 8 AN: 33480

American (AMR) AF: 0.000246 AC: 11 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000191 AC: 5 AN: 26134

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

South Asian (SAS) AF: 0.000939 AC: 81 AN: 86258

European-Finnish (FIN) AF: 0.000131 AC: 7 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.00132 AC: 1466 AN: 1112006

Other (OTH) AF: 0.000629 AC: 38 AN: 60396

GnomAD4 genome AF: 0.000722 AC: 110 AN: 152318 Hom.: 0 Cov.: 32 AF XY: 0.000752 AC XY: 56 AN XY: 74466

African (AFR) AF: 0.000193 AC: 8 AN: 41558

American (AMR) AF: 0.000392 AC: 6 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4822

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

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

European-Non Finnish (NFE) AF: 0.00129 AC: 88 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000962 Hom.: 0

Bravo AF: 0.000680

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00134 AC: 11

ExAC AF: 0.000820 AC: 99

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00104

EpiControl AF: 0.00124

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	Joubert syndrome 13 (3)
-	-	1	Inborn genetic diseases (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	0.32
BayesDel_addAF	Uncertain	0.021	T
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Uncertain	2.9	M
PhyloP100		2.3
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.013	D
Polyphen		0.97	D
Vest4		0.67
MutPred		0.65		Gain of catalytic residue at V427 (P = 0.0066)
MVP		0.88
MPC		0.60
ClinPred		0.080	T
GERP RS		5.2
Varity_R		0.23
gMVP		0.75
Mutation Taster		=82/18	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: rs188817098; hg19: chr12-111080154;