12-110632552-C-A

Position:

• chr12-110632552-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001082538.3(TCTN1):​c.705C>A​(p.Asn235Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TCTN1 NM_001082538.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.66

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]

TCTN1 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TCTN1	NM_001082538.3	c.705C>A	p.Asn235Lys	missense_variant	5/15	ENST00000397659.9	NP_001076007.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TCTN1	ENST00000397659.9	c.705C>A	p.Asn235Lys	missense_variant	5/15	1	NM_001082538.3	ENSP00000380779.4
TCTN1	ENST00000551590.5	c.705C>A	p.Asn235Lys	missense_variant	5/15	1		ENSP00000448735.1
TCTN1	ENST00000397655.7	c.705C>A	p.Asn235Lys	missense_variant	5/15	1		ENSP00000380775.3
TCTN1	ENST00000397656.8	n.*338C>A		non_coding_transcript_exon_variant	6/16	2		ENSP00000380776.4
TCTN1	ENST00000480648.5	n.705C>A		non_coding_transcript_exon_variant	5/16	5		ENSP00000437196.1
TCTN1	ENST00000495659.6	n.*463C>A		non_coding_transcript_exon_variant	5/15	2		ENSP00000436673.2
TCTN1	ENST00000397656.8	n.*338C>A		3_prime_UTR_variant	6/16	2		ENSP00000380776.4
TCTN1	ENST00000495659.6	n.*463C>A		3_prime_UTR_variant	5/15	2		ENSP00000436673.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000802 AC: 2 AN: 249532 Hom.: 0 AF XY: 0.00000739 AC XY: 1 AN XY: 135372

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000177

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461398 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727062

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000828 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	.;D;.;.;.
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.38
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.89	D;D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.83	D;D;D;D;D
MetaSVM	Uncertain	0.27	D
MutationAssessor	Pathogenic	3.0	.;M;M;M;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Pathogenic	-5.3	.;D;D;D;.
REVEL	Uncertain	0.64
Sift	Uncertain	0.0030	.;D;D;D;.
Sift4G	Uncertain	0.0050	D;D;D;D;D
Polyphen		1.0	.;D;D;D;.
Vest4		0.81
MutPred		0.66		Gain of ubiquitination at N235 (P = 0.0258);Gain of ubiquitination at N235 (P = 0.0258);Gain of ubiquitination at N235 (P = 0.0258);Gain of ubiquitination at N235 (P = 0.0258);.;
MVP		0.90
MPC		0.71
ClinPred		0.99	D
GERP RS		1.7
Varity_R		0.70
gMVP		0.72

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

Publications

LitVar

Other links and lift over

dbSNP: rs752181429; hg19: chr12-111070357;