17-74230963-C-G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_032646.6(TTYH2):c.378C>G(p.Asp126Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TTYH2 NM_032646.6 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0270

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]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04262665).
• BP6: Variant 17-74230963-C-G is Benign according to our data. Variant chr17-74230963-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 2316121.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TTYH2	NM_032646.6	c.378C>G	p.Asp126Glu	missense_variant	3/14	ENST00000269346.9
TTYH2	NM_001330453.2	c.315C>G	p.Asp105Glu	missense_variant	3/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TTYH2	ENST00000269346.9	c.378C>G	p.Asp126Glu	missense_variant	3/14	1	NM_032646.6	P1
TTYH2	ENST00000529107.5	c.315C>G	p.Asp105Glu	missense_variant	3/14	2
TTYH2	ENST00000578825.5	n.90C>G		non_coding_transcript_exon_variant	2/5	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
Cadd	Benign	0.51
Dann	Benign	0.66
DEOGEN2	Benign	0.029	T;T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.66	T;T
M_CAP	Benign	0.0024	T
MetaRNN	Benign	0.043	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.9	M;.
MutationTaster	Benign	0.78	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.12	N;N
REVEL	Benign	0.059
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0010	B;B
Vest4		0.099
MutPred		0.44		Gain of phosphorylation at Y123 (P = 0.1091);.;
MVP		0.030
MPC		0.12
ClinPred		0.047	T
GERP RS		-4.4
Varity_R		0.029
gMVP		0.34

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-72227102;