rs12366144

chr11-101476362-A-G

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.1683T>C(p.Asn561=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,812 control chromosomes in the GnomAD database, including 53,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8742 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45006 hom.)
• Consequence: TRPC6 NM_004621.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.17

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=-0.48).
• BP6: Variant 11-101476362-A-G is Benign according to our data. Variant chr11-101476362-A-G is described in ClinVar as [Benign]. Clinvar id is 259455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr11-101476362-A-G is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC6	NM_004621.6	c.1683T>C	p.Asn561=	synonymous_variant	6/13	ENST00000344327.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8	c.1683T>C	p.Asn561=	synonymous_variant	6/13	1	NM_004621.6	P1
TRPC6	ENST00000360497.4	c.1518T>C	p.Asn506=	synonymous_variant	5/12	1
TRPC6	ENST00000348423.8	c.1335T>C	p.Asn445=	synonymous_variant	4/11	1
TRPC6	ENST00000532133.5	c.1511-2589T>C		intron_variant		5

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46699 AN: 151942 Hom.: 8718 Cov.: 32

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.291

GnomAD3 exomes AF: 0.228 AC: 57351 AN: 251284 Hom.: 7985 AF XY: 0.230 AC XY: 31244 AN XY: 135802

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0455

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.240 AC: 351065 AN: 1461752 Hom.: 45006 Cov.: 36 AF XY: 0.241 AC XY: 174894 AN XY: 727174

Gnomad4 AFR exome AF: 0.555

Gnomad4 AMR exome AF: 0.141

Gnomad4 ASJ exome AF: 0.229

Gnomad4 EAS exome AF: 0.0971

Gnomad4 SAS exome AF: 0.257

Gnomad4 FIN exome AF: 0.201

Gnomad4 NFE exome AF: 0.239

Gnomad4 OTH exome AF: 0.254

GnomAD4 genome AF: 0.308 AC: 46775 AN: 152060 Hom.: 8742 Cov.: 32 AF XY: 0.301 AC XY: 22387 AN XY: 74314

Gnomad4 AFR AF: 0.533

Gnomad4 AMR AF: 0.198

Gnomad4 ASJ AF: 0.237

Gnomad4 EAS AF: 0.0583

Gnomad4 SAS AF: 0.244

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.241

Gnomad4 OTH AF: 0.296

Alfa AF: 0.271 Hom.: 2986

Bravo AF: 0.314

Asia WGS AF: 0.186 AC: 648 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.243

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 30, 2019	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Focal segmental glomerulosclerosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	5.3
Dann	Benign	0.61

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12366144; hg19: chr11-101347093; COSMIC: COSV60255434;