Genetic Variant TRPC5:p.Cys876Tyr (chrX-111776608-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012471.3(TRPC5):c.2627G>A(p.Cys876Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000223 in 1,210,328 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 13 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000024 ( 0 hom. 12 hem. )

Consequence

TRPC5
NM_012471.3 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 0.481

Publications

0 publications found

Variant links:

Genes affected

TRPC5 (HGNC:12337): (transient receptor potential cation channel subfamily C member 5) This gene belongs to the transient receptor family. It encodes one of the seven mammalian TRPC (transient receptor potential channel) proteins. The encoded protein is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF ), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1). [provided by RefSeq, May 2010]

TRPC5 Gene-Disease associations (from GenCC):

neurodevelopmental disorder
Inheritance: XL Classification: LIMITED Submitted by: G2P

TRPC5 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.034962684).

BS2

High Hemizygotes in GnomAdExome4 at 12 XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012471.3. 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
	TRPC5	NM_012471.3	MANE Select	c.2627G>A	p.Cys876Tyr	missense	Exon 11 of 11	NP_036603.1	Q9UL62

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC5	ENST00000262839.3	TSL:1 MANE Select	c.2627G>A	p.Cys876Tyr	missense	Exon 11 of 11	ENSP00000262839.2	Q9UL62

Frequencies

GnomAD3 genomes

AF:

0.00000892

AC:

AN:

112115

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000546

AC:

AN:

182987

AF XY:

0.00

show subpopulations

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000237

AC:

AN:

1098213

Hom.:

Cov.:

AF XY:

0.0000330

AC XY:

AN XY:

363581

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26399

American (AMR)

AF:

0.00

AC:

AN:

35205

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19386

East Asian (EAS)

AF:

0.00

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54146

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40526

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4137

European-Non Finnish (NFE)

AF:

0.0000285

AC:

AN:

842117

Other (OTH)

AF:

0.0000434

AC:

AN:

46096

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000892

AC:

AN:

112115

Hom.:

Cov.:

AF XY:

0.0000292

AC XY:

AN XY:

34269

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30827

American (AMR)

AF:

0.00

AC:

AN:

10542

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2642

East Asian (EAS)

AF:

0.00

AC:

AN:

3584

South Asian (SAS)

AF:

0.00

AC:

AN:

2671

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6142

Middle Eastern (MID)

AF:

0.00

AC:

AN:

239

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53271

Other (OTH)

AF:

0.00

AC:

AN:

1510

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000756

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

TRPC5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.80

CADD

Benign

3.0

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.61

M_CAP

Benign

0.0099

MetaRNN

Benign

0.035

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.55

PhyloP100

0.48

PrimateAI

Benign

0.38

PROVEAN

Benign

-0.43

REVEL

Benign

0.13

Sift

Benign

0.14

Sift4G

Uncertain

0.022

Polyphen

0.0

Vest4

0.031

MutPred

0.56

Gain of phosphorylation at C876 (P = 0.0483)

MVP

0.043

MPC

0.28

ClinPred

0.057

GERP RS

-1.7

Varity_R

0.093

gMVP

0.34

Mutation Taster

=87/13

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over