Variant 19-54436349-C-T details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001005367.3(TTYH1):c.1366C>T(p.Arg456Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000743 in 1,614,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00041 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

TTYH1
NM_001005367.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.00

Variant links:

Genes affected

TTYH1 (HGNC:13476): (tweety family member 1) This gene encodes a member of the tweety family of proteins. Members of this family function as chloride anion channels. The encoded protein functions as a calcium(2+)-independent, volume-sensitive large conductance chloride(-) channel. Three transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jan 2011]

TTYH1 links:

TTYH1 (HGNC:):

TTYH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.010943472).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTYH1	NM_020659.4 linkuse as main transcript	c.*59C>T		3_prime_UTR_variant	14/14	ENST00000376530.8	NP_065710.1	Q9H313-1
TTYH1	NM_001005367.3 linkuse as main transcript	c.1366C>T	p.Arg456Trp	missense_variant	13/13		NP_001005367.1	Q9H313-3
TTYH1	NM_001201461.2 linkuse as main transcript	c.*59C>T		3_prime_UTR_variant	14/14		NP_001188390.1	Q9H313-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTYH1	ENST00000376530.8 linkuse as main transcript	c.*59C>T		3_prime_UTR_variant	14/14	1	NM_020659.4	ENSP00000365713.3		Q9H313-1

Frequencies

GnomAD3 genomes

AF:

0.000407

AC:

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00142

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000638

AC:

AN:

250800

Hom.:

AF XY:

0.0000664

AC XY:

AN XY:

135604

show subpopulations

Gnomad AFR exome

AF:

0.000739

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461838

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

727230

show subpopulations

Gnomad4 AFR exome

AF:

0.000986

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000407

AC:

AN:

152332

Hom.:

Cov.:

AF XY:

0.000403

AC XY:

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00142

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000120

Hom.:

Bravo

AF:

0.000487

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000577

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 22, 2022

The c.1366C>T (p.R456W) alteration is located in exon 13 (coding exon 13) of the TTYH1 gene. This alteration results from a C to T substitution at nucleotide position 1366, causing the arginine (R) at amino acid position 456 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Uncertain

0.99

Eigen

Benign

-0.51

Eigen_PC

Benign

-0.47

FATHMM_MKL

Benign

0.41

M_CAP

Benign

0.053

MetaRNN

Benign

0.011

MetaSVM

Benign

-1.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.26

REVEL

Benign

0.061

Sift

Benign

0.032

Sift4G

Uncertain

0.042

Polyphen

0.0

Vest4

0.13

MVP

0.043

MPC

0.36

ClinPred

0.074

GERP RS

-1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

gMVP

0.54

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over