7-2646940-C-G

Variant names:

• chr7-2646940-C-G
• rs764868343
• NM_025250.3:c.211C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_025250.3(TTYH3):​c.211C>G​(p.Arg71Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000345 in 1,448,630 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R71L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000035 (0 hom.)
• Consequence: TTYH3 NM_025250.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.76
• Publications: 0 publications found

Genes affected

TTYH3 (HGNC:22222): (tweety family member 3) 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. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_025250.3. 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
	TTYH3	NM_025250.3	MANE Select	c.211C>G	p.Arg71Gly	missense	Exon 2 of 14	NP_079526.1	Q9C0H2-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TTYH3	ENST00000258796.12	TSL:1 MANE Select	c.211C>G	p.Arg71Gly	missense	Exon 2 of 14	ENSP00000258796.7	Q9C0H2-1
	TTYH3	ENST00000913086.1		c.520C>G	p.Arg174Gly	missense	Exon 3 of 15	ENSP00000583145.1
	TTYH3	ENST00000913085.1		c.211C>G	p.Arg71Gly	missense	Exon 2 of 15	ENSP00000583144.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000129 AC: 3 AN: 231786 AF XY: 0.00000788

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000590

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000345 AC: 5 AN: 1448630 Hom.: 0 Cov.: 43 AF XY: 0.00000139 AC XY: 1 AN XY: 720876

African (AFR) AF: 0.00 AC: 0 AN: 33434

American (AMR) AF: 0.0000450 AC: 2 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25986

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.0000117 AC: 1 AN: 85586

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 42938

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110788

Other (OTH) AF: 0.00 AC: 0 AN: 60110

GnomAD4 genome Cov.: 33

ExAC AF: 0.0000166 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.039	T
BayesDel_noAF	Uncertain	0.0
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.31	T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.55	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.8
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.28
Sift	Benign	0.29	T
Sift4G	Uncertain	0.059	T
Polyphen		1.0	D
Vest4		0.85
MutPred		0.53		Gain of ubiquitination at K74 (P = 0.0662)
MVP		0.21
MPC		0.43
ClinPred		0.71	D
GERP RS		5.0
Varity_R		0.56
gMVP		0.69
Mutation Taster		=40/60	disease causing

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: rs764868343; hg19: chr7-2686574; COSMIC: COSV104991627; COSMIC: COSV104991627;