rs12805398

Variant names:

• chr11-101453039-C-T
• rs12805398
• NM_004621.6:c.2712G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004621.6(TRPC6):​c.2712G>A​(p.Gln904Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,612 control chromosomes in the GnomAD database, including 12,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (842 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11487 hom.)
• Consequence: TRPC6 NM_004621.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0810
• Publications: 12 publications found

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

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 11-101453039-C-T is Benign according to our data. Variant chr11-101453039-C-T is described in ClinVar as Benign. ClinVar VariationId is 259462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.081 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.2712G>A	p.Gln904Gln	synonymous_variant	Exon 13 of 13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.2712G>A	p.Gln904Gln	synonymous_variant	Exon 13 of 13	1	NM_004621.6	ENSP00000340913.3
TRPC6	ENST00000360497.4	c.2547G>A	p.Gln849Gln	synonymous_variant	Exon 12 of 12	1		ENSP00000353687.4
TRPC6	ENST00000348423.8	c.2364G>A	p.Gln788Gln	synonymous_variant	Exon 11 of 11	1		ENSP00000343672.4
TRPC6	ENST00000532133.5	c.2478G>A	p.Gln826Gln	synonymous_variant	Exon 12 of 12	5		ENSP00000435574.1

Frequencies

GnomAD3 genomes AF: 0.0901 AC: 13702 AN: 152096 Hom.: 840 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0750

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.104 AC: 26050 AN: 251026 AF XY: 0.109

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.0562

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0521

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.122 AC: 178699 AN: 1461398 Hom.: 11487 Cov.: 32 AF XY: 0.123 AC XY: 89468 AN XY: 726996

African (AFR) AF: 0.0239 AC: 801 AN: 33466

American (AMR) AF: 0.0610 AC: 2725 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3792 AN: 26114

East Asian (EAS) AF: 0.116 AC: 4592 AN: 39672

South Asian (SAS) AF: 0.114 AC: 9822 AN: 86248

European-Finnish (FIN) AF: 0.103 AC: 5509 AN: 53392

Middle Eastern (MID) AF: 0.149 AC: 861 AN: 5764

European-Non Finnish (NFE) AF: 0.129 AC: 143405 AN: 1111666

Other (OTH) AF: 0.119 AC: 7192 AN: 60374

GnomAD4 genome AF: 0.0900 AC: 13699 AN: 152214 Hom.: 842 Cov.: 32 AF XY: 0.0891 AC XY: 6631 AN XY: 74416

African (AFR) AF: 0.0260 AC: 1079 AN: 41564

American (AMR) AF: 0.0749 AC: 1145 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 491 AN: 3468

East Asian (EAS) AF: 0.0629 AC: 324 AN: 5152

South Asian (SAS) AF: 0.0981 AC: 473 AN: 4820

European-Finnish (FIN) AF: 0.0998 AC: 1058 AN: 10600

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8773 AN: 68000

Other (OTH) AF: 0.105 AC: 221 AN: 2112

Alfa AF: 0.117 Hom.: 549

Bravo AF: 0.0846

Asia WGS AF: 0.0680 AC: 237 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.133

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Apr 12, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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 20% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 19. Only high quality variants are reported. -

Focal segmental glomerulosclerosis 2 Benign:1

Jan 13, 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
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.1
DANN	Benign	0.55
PhyloP100		-0.081
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12805398; hg19: chr11-101323770; COSMIC: COSV60254838; COSMIC: COSV60254838;