rs59743346

Positions:

• chr11-101453125-TAAG-T
• chr11-101453125-TAAG-TAAGAAG

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004621.6(TRPC6):​c.2645-22_2645-20del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,609,060 control chromosomes in the GnomAD database, including 51,845 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.31 (9656 hom., cov: 0)
  • Exomes 𝑓: 0.23 (42189 hom.)
• Consequence: TRPC6 NM_004621.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.640

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 -16 ACMG points.

• BP6: Variant 11-101453125-TAAG-T is Benign according to our data. Variant chr11-101453125-TAAG-T is described in ClinVar as [Benign]. Clinvar id is 259461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC6	NM_004621.6	c.2645-22_2645-20del		intron_variant		ENST00000344327.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8	c.2645-22_2645-20del		intron_variant		1	NM_004621.6	P1
TRPC6	ENST00000348423.8	c.2297-22_2297-20del		intron_variant		1
TRPC6	ENST00000360497.4	c.2480-22_2480-20del		intron_variant		1
TRPC6	ENST00000532133.5	c.2411-22_2411-20del		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47358 AN: 151728 Hom.: 9618 Cov.: 0

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.0646

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.302

GnomAD3 exomes AF: 0.222 AC: 55406 AN: 250076 Hom.: 7824 AF XY: 0.222 AC XY: 30016 AN XY: 135224

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.0529

Gnomad SAS exome AF: 0.245

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.229 AC: 333812 AN: 1457214 Hom.: 42189 AF XY: 0.229 AC XY: 166351 AN XY: 725118

Gnomad4 AFR exome AF: 0.611

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.258

Gnomad4 EAS exome AF: 0.116

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.156

Gnomad4 NFE exome AF: 0.225

Gnomad4 OTH exome AF: 0.247

GnomAD4 genome AF: 0.312 AC: 47451 AN: 151846 Hom.: 9656 Cov.: 0 AF XY: 0.304 AC XY: 22588 AN XY: 74188

Gnomad4 AFR AF: 0.586

Gnomad4 AMR AF: 0.196

Gnomad4 ASJ AF: 0.259

Gnomad4 EAS AF: 0.0641

Gnomad4 SAS AF: 0.226

Gnomad4 FIN AF: 0.150

Gnomad4 NFE AF: 0.227

Gnomad4 OTH AF: 0.308

Alfa AF: 0.272 Hom.: 1253

Bravo AF: 0.326

Asia WGS AF: 0.189 AC: 659 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 41% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 38. Only high quality variants are reported. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -

Focal segmental glomerulosclerosis 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 04, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 10, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BranchPoint Hunter		4.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs59743346; hg19: chr11-101323856;