rs72984209

Positions:

• chr11-101455057-G-A
• chr11-101455057-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000344327.8(TRPC6):​c.2529C>T​(p.Phe843=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0848 in 1,610,434 control chromosomes in the GnomAD database, including 9,280 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.15 (2912 hom., cov: 32)
  • Exomes 𝑓: 0.078 (6368 hom.)
• Consequence: TRPC6 ENST00000344327.8 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.187

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BP6: Variant 11-101455057-G-A is Benign according to our data. Variant chr11-101455057-G-A is described in ClinVar as [Benign]. Clinvar id is 259460.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-101455057-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.187 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.345 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.2529C>T	p.Phe843=	synonymous_variant	11/13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.2529C>T	p.Phe843=	synonymous_variant	11/13	1	NM_004621.6	ENSP00000340913	P1

Frequencies

GnomAD3 genomes AF: 0.148 AC: 22460 AN: 151944 Hom.: 2903 Cov.: 32

Gnomad AFR AF: 0.350

Gnomad AMI AF: 0.103

Gnomad AMR AF: 0.0903

Gnomad ASJ AF: 0.0810

Gnomad EAS AF: 0.000769

Gnomad SAS AF: 0.0808

Gnomad FIN AF: 0.0438

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.0742

Gnomad OTH AF: 0.139

GnomAD3 exomes AF: 0.0826 AC: 20712 AN: 250668 Hom.: 1626 AF XY: 0.0797 AC XY: 10793 AN XY: 135484

Gnomad AFR exome AF: 0.353

Gnomad AMR exome AF: 0.0564

Gnomad ASJ exome AF: 0.0912

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0808

Gnomad FIN exome AF: 0.0430

Gnomad NFE exome AF: 0.0723

Gnomad OTH exome AF: 0.0868

GnomAD4 exome AF: 0.0782 AC: 114024 AN: 1458372 Hom.: 6368 Cov.: 30 AF XY: 0.0778 AC XY: 56438 AN XY: 725578

Gnomad4 AFR exome AF: 0.365

Gnomad4 AMR exome AF: 0.0612

Gnomad4 ASJ exome AF: 0.0810

Gnomad4 EAS exome AF: 0.000152

Gnomad4 SAS exome AF: 0.0792

Gnomad4 FIN exome AF: 0.0438

Gnomad4 NFE exome AF: 0.0736

Gnomad4 OTH exome AF: 0.0892

GnomAD4 genome AF: 0.148 AC: 22503 AN: 152062 Hom.: 2912 Cov.: 32 AF XY: 0.143 AC XY: 10648 AN XY: 74336

Gnomad4 AFR AF: 0.350

Gnomad4 AMR AF: 0.0902

Gnomad4 ASJ AF: 0.0810

Gnomad4 EAS AF: 0.000771

Gnomad4 SAS AF: 0.0809

Gnomad4 FIN AF: 0.0438

Gnomad4 NFE AF: 0.0742

Gnomad4 OTH AF: 0.138

Alfa AF: 0.0952 Hom.: 653

Bravo AF: 0.159

Asia WGS AF: 0.0580 AC: 202 AN: 3474

EpiCase AF: 0.0804

EpiControl AF: 0.0841

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 28, 2024	- -

Focal segmental glomerulosclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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. -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	3.0
DANN	Benign	0.45

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

Other links and lift over

dbSNP: rs72984209; hg19: chr11-101325788; COSMIC: COSV60255420;