Variant chr17-74222543-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032646.6(TTYH2):c.188T>C(p.Leu63Pro) variant causes a missense change. The variant allele was found at a frequency of 0.0000651 in 1,612,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

TTYH2
NM_032646.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.09

Variant links:

Genes affected

TTYH2 (HGNC:13877): (tweety family member 2) 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+)-activated large conductance chloride(-) channel, and may play a role in kidney tumorigenesis. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

TTYH2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TTYH2	NM_032646.6 linkuse as main transcript	c.188T>C	p.Leu63Pro	missense_variant	2/14	ENST00000269346.9	NP_116035.5
TTYH2	NM_001330453.2 linkuse as main transcript	c.125T>C	p.Leu42Pro	missense_variant	2/14		NP_001317382.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TTYH2	ENST00000269346.9 linkuse as main transcript	c.188T>C	p.Leu63Pro	missense_variant	2/14	1	NM_032646.6	ENSP00000269346	P1	Q9BSA4-1
TTYH2	ENST00000529107.5 linkuse as main transcript	c.125T>C	p.Leu42Pro	missense_variant	2/14	2		ENSP00000433089

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152226

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

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:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000560

AC:

AN:

249924

Hom.:

AF XY:

0.0000517

AC XY:

AN XY:

135294

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.000231

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:

0.0000265

Gnomad OTH exome

AF:

0.000327

GnomAD4 exome

AF:

0.0000651

AC:

AN:

1460338

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

726580

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000268

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000674

Gnomad4 OTH exome

AF:

0.0000994

GnomAD4 genome

AF:

0.0000656

AC:

AN:

152344

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74500

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000131

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000967

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000412

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.0000593

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

Aug 30, 2021

The c.188T>C (p.L63P) alteration is located in exon 2 (coding exon 2) of the TTYH2 gene. This alteration results from a T to C substitution at nucleotide position 188, causing the leucine (L) at amino acid position 63 to be replaced by a proline (P). 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

AlphaMissense

Uncertain

0.38

BayesDel_addAF

Benign

-0.026

BayesDel_noAF

Uncertain

0.020

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.34

T;T

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Benign

0.74

T;T

M_CAP

Uncertain

0.14

MetaRNN

Pathogenic

0.89

D;D

MetaSVM

Benign

-0.77

MutationAssessor

Pathogenic

3.1

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.59

PROVEAN

Pathogenic

-5.3

D;D

REVEL

Uncertain

0.51

Sift

Pathogenic

0.0

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

0.99

D;D

Vest4

0.87

MVP

0.34

MPC

0.72

ClinPred

0.91

GERP RS

5.5

Varity_R

0.94

gMVP

0.94

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

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