Genetic Variant TRPC5:p.Arg835Cys (chrX-111776732-G-A) – 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.2503C>T(p.Arg835Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000198 in 1,209,917 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 9 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000054 ( 0 hom., 3 hem., cov: 23)

Exomes 𝑓: 0.000016 ( 0 hom. 6 hem. )

Consequence

TRPC5
NM_012471.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1B:1

Conservation

PhyloP100: 4.77

Publications

2 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=0.016036123).

BS2

High Hemizygotes in GnomAd4 at 3 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.2503C>T	p.Arg835Cys	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.2503C>T	p.Arg835Cys	missense	Exon 11 of 11	ENSP00000262839.2	Q9UL62

Frequencies

GnomAD3 genomes

AF:

0.0000536

AC:

AN:

111949

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:

0.00169

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

GnomAD2 exomes

AF:

0.000104

AC:

AN:

182477

AF XY:

0.000104

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000366

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00130

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000164

AC:

AN:

1097914

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

363296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26392

American (AMR)

AF:

0.0000284

AC:

AN:

35177

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19351

East Asian (EAS)

AF:

0.000497

AC:

AN:

30201

South Asian (SAS)

AF:

0.00

AC:

AN:

54057

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40520

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4131

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

841997

Other (OTH)

AF:

0.0000434

AC:

AN:

46088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.0000536

AC:

AN:

112003

Hom.:

Cov.:

AF XY:

0.0000878

AC XY:

AN XY:

34167

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30869

American (AMR)

AF:

0.00

AC:

AN:

10547

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2649

East Asian (EAS)

AF:

0.00170

AC:

AN:

3533

South Asian (SAS)

AF:

0.00

AC:

AN:

2651

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6099

Middle Eastern (MID)

AF:

0.00

AC:

AN:

217

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

53215

Other (OTH)

AF:

0.00

AC:

AN:

1535

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.542

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome 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

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000453

ExAC

AF:

0.0000741

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

TRPC5-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.28

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.016

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.34

PhyloP100

4.8

PrimateAI

Benign

0.47

PROVEAN

Benign

-2.2

REVEL

Benign

0.096

Sift

Uncertain

0.0070

Sift4G

Uncertain

0.020

Polyphen

0.0010

Vest4

0.10

MutPred

0.34

Loss of MoRF binding (P = 0.0033)

MVP

0.40

MPC

0.29

ClinPred

0.12

GERP RS

4.8

Varity_R

0.23

gMVP

0.54

Mutation Taster

=92/8

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over