11-101583757-G-C

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_004621.6(TRPC6):c.-254C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 394,526 control chromosomes in the GnomAD database, including 4,279 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.098 ( 1292 hom., cov: 33)

Exomes 𝑓: 0.12 ( 2987 hom. )

Consequence

TRPC6
NM_004621.6 5_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.330

Publications

18 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 -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6 link	c.-254C>G	5_prime_UTR_variant	Exon 1 of 13	ENST00000344327.8	NP_004612.2	Q9Y210-1
TRPC6	NM_001439335.1 link	c.-254C>G	5_prime_UTR_variant	Exon 1 of 11		NP_001426264.1
TRPC6	XM_047427510.1 link	c.-254C>G	5_prime_UTR_variant	Exon 1 of 11		XP_047283466.1
TRPC6	XM_047427509.1 link	c.-89+175C>G	intron_variant	Intron 1 of 12		XP_047283465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8 link	c.-254C>G		5_prime_UTR_variant	Exon 1 of 13	1	NM_004621.6	ENSP00000340913.3		Q9Y210-1
TRPC6	ENST00000526713.1 link	n.266-78959C>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes

AF:

0.0975

AC:

14841

AN:

152140

Hom.:

1284

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0379

Gnomad AMI

AF:

0.00548

Gnomad AMR

AF:

0.162

Gnomad ASJ

AF:

0.0922

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.268

Gnomad FIN

AF:

0.103

Gnomad MID

AF:

0.0854

Gnomad NFE

AF:

0.0804

Gnomad OTH

AF:

0.102

GnomAD4 exome

AF:

0.119

AC:

28829

AN:

242268

Hom.:

2987

Cov.:

AF XY:

0.117

AC XY:

14465

AN XY:

123120

show subpopulations

African (AFR)

AF:

0.0381

AC:

257

AN:

6750

American (AMR)

AF:

0.183

AC:

1280

AN:

6984

Ashkenazi Jewish (ASJ)

AF:

0.0938

AC:

833

AN:

8880

East Asian (EAS)

AF:

0.423

AC:

9113

AN:

21560

South Asian (SAS)

AF:

0.235

AC:

1057

AN:

4498

European-Finnish (FIN)

AF:

0.0985

AC:

1983

AN:

20140

Middle Eastern (MID)

AF:

0.0730

AC:

AN:

1246

European-Non Finnish (NFE)

AF:

0.0796

AC:

12458

AN:

156434

Other (OTH)

AF:

0.111

AC:

1757

AN:

15776

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

1070

2140

3211

4281

5351

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0976

AC:

14859

AN:

152258

Hom.:

1292

Cov.:

AF XY:

0.105

AC XY:

7794

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.0378

AC:

1570

AN:

41572

American (AMR)

AF:

0.162

AC:

2480

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0922

AC:

320

AN:

3472

East Asian (EAS)

AF:

0.463

AC:

2379

AN:

5136

South Asian (SAS)

AF:

0.268

AC:

1294

AN:

4824

European-Finnish (FIN)

AF:

0.103

AC:

1094

AN:

10616

Middle Eastern (MID)

AF:

0.0884

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0804

AC:

5465

AN:

68012

Other (OTH)

AF:

0.107

AC:

226

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

641

1281

1922

2562

3203

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0906

Hom.:

Bravo

AF:

0.0996

Asia WGS

AF:

0.360

AC:

1251

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Nov 12, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 31281825, 19380626, 23999069, 25603901) -

Atypical hemolytic-uremic syndrome

Benign:1

Aug 12, 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

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

4.1

(source)

DANN

Benign

0.73

PhyloP100

-0.33

PromoterAI

0.023

Neutral

(source)

Mutation Taster

=300/0

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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11-101583757-G-C

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