Genetic Variant TRPC5:p.Glu892Lys (chrX-111776561-C-T) – ACMG Classification: Benign (-9 pts)

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_012471.3(TRPC5):c.2674G>A(p.Glu892Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000611 in 1,210,333 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 21 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (no stars).

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., 10 hem., cov: 23)

Exomes 𝑓: 0.000032 ( 0 hom. 11 hem. )

Consequence

TRPC5
NM_012471.3 missense

Scores

Clinical Significance

Likely benign no assertion criteria provided B:1

Conservation

PhyloP100: 3.83

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.01908049).

BP6

Variant X-111776561-C-T is Benign according to our data. Variant chrX-111776561-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3042876.Status of the report is no_assertion_criteria_provided, 0 stars.

BS2

High Hemizygotes in GnomAd4 at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC5	NM_012471.3 link	c.2674G>A	p.Glu892Lys	missense_variant	Exon 11 of 11	ENST00000262839.3	NP_036603.1	Q9UL62
TRPC5	XM_017029774.2 link	c.2674G>A	p.Glu892Lys	missense_variant	Exon 12 of 12		XP_016885263.1	Q9UL62

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC5	ENST00000262839.3 link	c.2674G>A	p.Glu892Lys	missense_variant	Exon 11 of 11	1	NM_012471.3	ENSP00000262839.2		Q9UL62

Frequencies

GnomAD3 genomes

AF:

0.000339

AC:

AN:

112163

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

AN XY:

34311

show subpopulations

Gnomad AFR

AF:

0.00117

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000945

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:

0.00

Gnomad OTH

AF:

0.000658

GnomAD3 exomes

AF:

0.0000985

AC:

AN:

182699

Hom.:

AF XY:

0.0000742

AC XY:

AN XY:

67403

show subpopulations

Gnomad AFR exome

AF:

0.00122

Gnomad AMR exome

AF:

0.00

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:

0.0000246

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000319

AC:

AN:

1098116

Hom.:

Cov.:

AF XY:

0.0000303

AC XY:

AN XY:

363496

show subpopulations

Gnomad4 AFR exome

AF:

0.00110

Gnomad4 AMR exome

AF:

0.0000568

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000238

Gnomad4 OTH exome

AF:

0.0000434

GnomAD4 genome

AF:

0.000348

AC:

AN:

112217

Hom.:

Cov.:

AF XY:

0.000291

AC XY:

AN XY:

34375

show subpopulations

Gnomad4 AFR

AF:

0.00120

Gnomad4 AMR

AF:

0.0000944

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000650

Alfa

AF:

0.000272

Hom.:

Bravo

AF:

0.000351

ESP6500AA

AF:

0.000261

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000115

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

TRPC5-related disorder

Benign:1

Mar 30, 2022

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.16

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.80

M_CAP

Benign

0.029

MetaRNN

Benign

0.019

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.51

PROVEAN

Benign

0.010

REVEL

Benign

0.24

Sift

Benign

0.11

Sift4G

Benign

0.30

Polyphen

0.24

Vest4

0.15

MVP

0.64

MPC

0.18

ClinPred

0.051

GERP RS

5.6

Varity_R

0.29

gMVP

0.20

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