rs61743044

Positions:

• chr11-101472227-G-A

Variant summary

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

The NM_004621.6(TRPC6):​c.2115C>T​(p.Tyr705=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,612,978 control chromosomes in the GnomAD database, including 727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (248 hom., cov: 32)
  • Exomes 𝑓: 0.022 (479 hom.)
• Consequence: TRPC6 NM_004621.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.453

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=-0.5).
• BP6: Variant 11-101472227-G-A is Benign according to our data. Variant chr11-101472227-G-A is described in ClinVar as [Benign]. Clinvar id is 259458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-101472227-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.453 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0997 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC6	NM_004621.6	c.2115C>T	p.Tyr705=	synonymous_variant	8/13	ENST00000344327.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8	c.2115C>T	p.Tyr705=	synonymous_variant	8/13	1	NM_004621.6	P1
TRPC6	ENST00000360497.4	c.1950C>T	p.Tyr650=	synonymous_variant	7/12	1
TRPC6	ENST00000348423.8	c.1767C>T	p.Tyr589=	synonymous_variant	6/11	1
TRPC6	ENST00000532133.5	c.1881C>T	p.Tyr627=	synonymous_variant	7/12	5

Frequencies

GnomAD3 genomes AF: 0.0411 AC: 6245 AN: 152062 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0296

GnomAD3 exomes AF: 0.0200 AC: 4996 AN: 250108 Hom.: 140 AF XY: 0.0182 AC XY: 2458 AN XY: 135220

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.00988

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00649

Gnomad FIN exome AF: 0.00755

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0216 AC: 31622 AN: 1460798 Hom.: 479 Cov.: 31 AF XY: 0.0208 AC XY: 15110 AN XY: 726706

Gnomad4 AFR exome AF: 0.109

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0247

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00695

Gnomad4 FIN exome AF: 0.00852

Gnomad4 NFE exome AF: 0.0217

Gnomad4 OTH exome AF: 0.0252

GnomAD4 genome AF: 0.0411 AC: 6258 AN: 152180 Hom.: 248 Cov.: 32 AF XY: 0.0388 AC XY: 2886 AN XY: 74384

Gnomad4 AFR AF: 0.102

Gnomad4 AMR AF: 0.0183

Gnomad4 ASJ AF: 0.0265

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00580

Gnomad4 FIN AF: 0.00624

Gnomad4 NFE AF: 0.0218

Gnomad4 OTH AF: 0.0293

Alfa AF: 0.0312 Hom.: 73

Bravo AF: 0.0444

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0198

EpiControl AF: 0.0191

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 25, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 12, 2020	- -

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	May 15, 2017	- -

Focal segmental glomerulosclerosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 18, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.4
DANN	Benign	0.47

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61743044; hg19: chr11-101342958; COSMIC: COSV60252389;