rs36111323

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -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. 12/21 in silico tools predict 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:8

Conservation

PhyloP100: 4.84

Publications

30 publications found

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 Gene-Disease associations (from GenCC):

focal segmental glomerulosclerosis 2
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
familial idiopathic steroid-resistant nephrotic syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TRPC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TRPC6	NM_004621.6 link	c.1211C>T	p.Ala404Val	missense_variant	Exon 4 of 13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
TRPC6	ENST00000344327.8 link	c.1211C>T	p.Ala404Val	missense_variant	Exon 4 of 13	1	NM_004621.6	ENSP00000340913.3
TRPC6	ENST00000360497.4 link	c.1128+2537C>T		intron_variant	Intron 3 of 11	1		ENSP00000353687.4
TRPC6	ENST00000348423.8 link	c.946-5854C>T		intron_variant	Intron 2 of 10	1		ENSP00000343672.4
TRPC6	ENST00000532133.5 link	c.1211C>T	p.Ala404Val	missense_variant	Exon 4 of 12	5		ENSP00000435574.1

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

GnomAD2 exomes

AF:

0.0954

AC:

23989

AN:

251350

AF XY:

0.101

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 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

African (AFR)

AF:

0.0188

AC:

631

AN:

33480

American (AMR)

AF:

0.0594

AC:

2656

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.105

AC:

2747

AN:

26130

East Asian (EAS)

AF:

0.0561

AC:

2226

AN:

39694

South Asian (SAS)

AF:

0.122

AC:

10487

AN:

86256

European-Finnish (FIN)

AF:

0.101

AC:

5383

AN:

53418

Middle Eastern (MID)

AF:

0.112

AC:

644

AN:

5764

European-Non Finnish (NFE)

AF:

0.122

AC:

135852

AN:

1111932

Other (OTH)

AF:

0.110

AC:

6654

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

8566

17133

25699

34266

42832

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4746

9492

14238

18984

23730

<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:

0.0829

AC:

12628

AN:

152282

Hom.:

716

Cov.:

AF XY:

0.0825

AC XY:

6146

AN XY:

74468

show subpopulations

African (AFR)

AF:

0.0214

AC:

889

AN:

41572

American (AMR)

AF:

0.0743

AC:

1137

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.107

AC:

370

AN:

3472

East Asian (EAS)

AF:

0.0235

AC:

122

AN:

5182

South Asian (SAS)

AF:

0.108

AC:

520

AN:

4826

European-Finnish (FIN)

AF:

0.0987

AC:

1046

AN:

10598

Middle Eastern (MID)

AF:

0.126

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.121

AC:

8218

AN:

68018

Other (OTH)

AF:

0.0901

AC:

190

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

598

1196

1794

2392

2990

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

288

432

576

720

<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:

0.108

Hom.:

3697

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:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

Apr 14, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 25, 2019

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 19701773, 26127002, 26892346, 28476686) -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Sep 27, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Focal segmental glomerulosclerosis 2

Benign:1

Mar 06, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

(source)

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;.

PhyloP100

4.8

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

Mutation Taster

=83/17

polymorphism (auto)

(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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over