rs36111323

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004621.6(TRPC6):c.1211C>T(p.Ala404Val) variant causes a missense change. The variant allele was found at a frequency of 0.111 in 1,614,072 control chromosomes in the GnomAD database, including 10,911 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. A404A) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.083 ( 716 hom., cov: 33)

Exomes 𝑓: 0.11 ( 10195 hom. )

Consequence

TRPC6
NM_004621.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 4.84

Variant links:

Genes affected

TRPC6 (HGNC:12338): (transient receptor potential cation channel subfamily C member 6) The protein encoded by this gene forms a receptor-activated calcium channel in the cell membrane. The channel is activated by diacylglycerol and is thought to be under the control of a phosphatidylinositol second messenger system. Activation of this channel occurs independently of protein kinase C and is not triggered by low levels of intracellular calcium. Defects in this gene are a cause of focal segmental glomerulosclerosis 2 (FSGS2). [provided by RefSeq, Mar 2009]

TRPC6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0019279122).

BP6

Variant 11-101489019-G-A is Benign according to our data. Variant chr11-101489019-G-A is described in ClinVar as [Benign]. Clinvar id is 259454.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC6	NM_004621.6 linkuse as main transcript	c.1211C>T	p.Ala404Val	missense_variant	4/13	ENST00000344327.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8 linkuse as main transcript	c.1211C>T	p.Ala404Val	missense_variant	4/13	1	NM_004621.6	P1	Q9Y210-1
TRPC6	ENST00000348423.8 linkuse as main transcript	c.946-5854C>T		intron_variant		1			Q9Y210-2
TRPC6	ENST00000360497.4 linkuse as main transcript	c.1128+2537C>T		intron_variant		1			Q9Y210-3
TRPC6	ENST00000532133.5 linkuse as main transcript	c.1211C>T	p.Ala404Val	missense_variant	4/12	5

Frequencies

GnomAD3 genomes

AF:

0.0830

AC:

12635

AN:

152164

Hom.:

714

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0214

Gnomad AMI

AF:

0.109

Gnomad AMR

AF:

0.0744

Gnomad ASJ

AF:

0.107

Gnomad EAS

AF:

0.0237

Gnomad SAS

AF:

0.108

Gnomad FIN

AF:

0.0987

Gnomad MID

AF:

0.127

Gnomad NFE

AF:

0.121

Gnomad OTH

AF:

0.0906

GnomAD3 exomes

AF:

0.0954

AC:

23989

AN:

251350

Hom.:

1357

AF XY:

0.101

AC XY:

13763

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.0186

Gnomad AMR exome

AF:

0.0552

Gnomad ASJ exome

AF:

0.106

Gnomad EAS exome

AF:

0.00827

Gnomad SAS exome

AF:

0.121

Gnomad FIN exome

AF:

0.0981

Gnomad NFE exome

AF:

0.124

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.114

AC:

167280

AN:

1461790

Hom.:

10195

Cov.:

AF XY:

0.116

AC XY:

84129

AN XY:

727192

show subpopulations

Gnomad4 AFR exome

AF:

0.0188

Gnomad4 AMR exome

AF:

0.0594

Gnomad4 ASJ exome

AF:

0.105

Gnomad4 EAS exome

AF:

0.0561

Gnomad4 SAS exome

AF:

0.122

Gnomad4 FIN exome

AF:

0.101

Gnomad4 NFE exome

AF:

0.122

Gnomad4 OTH exome

AF:

0.110

GnomAD4 genome

AF:

0.0829

AC:

12628

AN:

152282

Hom.:

716

Cov.:

AF XY:

0.0825

AC XY:

6146

AN XY:

74468

show subpopulations

Gnomad4 AFR

AF:

0.0214

Gnomad4 AMR

AF:

0.0743

Gnomad4 ASJ

AF:

0.107

Gnomad4 EAS

AF:

0.0235

Gnomad4 SAS

AF:

0.108

Gnomad4 FIN

AF:

0.0987

Gnomad4 NFE

AF:

0.121

Gnomad4 OTH

AF:

0.0901

Alfa

AF:

0.109

Hom.:

1618

Bravo

AF:

0.0761

TwinsUK

AF:

0.113

AC:

420

ALSPAC

AF:

0.118

AC:

456

ESP6500AA

AF:

0.0227

AC:

100

ESP6500EA

AF:

0.122

AC:

1047

ExAC

AF:

0.0985

AC:

11961

Asia WGS

AF:

0.0490

AC:

172

AN:

3478

EpiCase

AF:

0.126

EpiControl

AF:

0.121

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 25, 2019	This variant is associated with the following publications: (PMID: 19701773, 26127002, 26892346, 28476686) -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 23% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 21. Only high quality variants are reported. -

Focal segmental glomerulosclerosis

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Sep 27, 2022

- -

Focal segmental glomerulosclerosis 2

Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 06, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.38

CADD

Uncertain

DANN

Benign

0.97

DEOGEN2

Benign

0.29

T;.

Eigen

Uncertain

0.20

Eigen_PC

Benign

0.20

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.86

D;D

MetaRNN

Benign

0.0019

T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

L;.

MutationTaster

Benign

7.2e-7

P;P;P;P

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.21

Sift

Benign

0.32

T;T

Sift4G

Benign

0.58

T;T

Polyphen

1.0

D;.

Vest4

0.33

MPC

0.30

ClinPred

0.033

GERP RS

3.9

Varity_R

0.17

gMVP

0.37

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