rs3802829

Positions:

• chr11-101583461-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004621.6(TRPC6):​c.43C>T​(p.Pro15Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 1,531,530 control chromosomes in the GnomAD database, including 8,033 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (524 hom., cov: 33)
  • Exomes 𝑓: 0.10 (7509 hom.)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.11

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017862916).
• BP6: Variant 11-101583461-G-A is Benign according to our data. Variant chr11-101583461-G-A is described in ClinVar as [Benign]. Clinvar id is 259463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.102 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC6	NM_004621.6	c.43C>T	p.Pro15Ser	missense_variant	1/13	ENST00000344327.8
TRPC6	XM_047427510.1	c.43C>T	p.Pro15Ser	missense_variant	1/11
TRPC6	XM_017018221.3	c.43C>T	p.Pro15Ser	missense_variant	1/11
TRPC6	XM_047427509.1	c.-89+471C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8	c.43C>T	p.Pro15Ser	missense_variant	1/13	1	NM_004621.6	P1

Frequencies

GnomAD3 genomes AF: 0.0719 AC: 10941 AN: 152198 Hom.: 525 Cov.: 33

Gnomad AFR AF: 0.0178

Gnomad AMI AF: 0.0406

Gnomad AMR AF: 0.0749

Gnomad ASJ AF: 0.0910

Gnomad EAS AF: 0.106

Gnomad SAS AF: 0.0601

Gnomad FIN AF: 0.0545

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.104

Gnomad OTH AF: 0.0879

GnomAD3 exomes AF: 0.0822 AC: 11147 AN: 135616 Hom.: 581 AF XY: 0.0846 AC XY: 6229 AN XY: 73614

Gnomad AFR exome AF: 0.0190

Gnomad AMR exome AF: 0.0573

Gnomad ASJ exome AF: 0.0894

Gnomad EAS exome AF: 0.0899

Gnomad SAS exome AF: 0.0741

Gnomad FIN exome AF: 0.0615

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.103

GnomAD4 exome AF: 0.101 AC: 139875 AN: 1379216 Hom.: 7509 Cov.: 32 AF XY: 0.101 AC XY: 68468 AN XY: 678714

Gnomad4 AFR exome AF: 0.0163

Gnomad4 AMR exome AF: 0.0601

Gnomad4 ASJ exome AF: 0.0891

Gnomad4 EAS exome AF: 0.128

Gnomad4 SAS exome AF: 0.0730

Gnomad4 FIN exome AF: 0.0638

Gnomad4 NFE exome AF: 0.108

Gnomad4 OTH exome AF: 0.102

GnomAD4 genome AF: 0.0718 AC: 10936 AN: 152314 Hom.: 524 Cov.: 33 AF XY: 0.0693 AC XY: 5159 AN XY: 74468

Gnomad4 AFR AF: 0.0178

Gnomad4 AMR AF: 0.0748

Gnomad4 ASJ AF: 0.0910

Gnomad4 EAS AF: 0.105

Gnomad4 SAS AF: 0.0602

Gnomad4 FIN AF: 0.0545

Gnomad4 NFE AF: 0.104

Gnomad4 OTH AF: 0.0865

Alfa AF: 0.0906 Hom.: 166

Bravo AF: 0.0702

TwinsUK AF: 0.110 AC: 408

ALSPAC AF: 0.111 AC: 427

ESP6500AA AF: 0.0187 AC: 76

ESP6500EA AF: 0.0860 AC: 680

ExAC AF: 0.0428 AC: 4203

Asia WGS AF: 0.0590 AC: 206 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 23, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

Focal segmental glomerulosclerosis 2 Benign:2

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. -
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
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	18
DANN	Benign	0.96
DEOGEN2	Benign	0.24	T;.;.;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Benign	0.82	T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;.;N;N
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.80	N;N;N;N
REVEL	Uncertain	0.33
Sift	Benign	0.049	D;D;D;D
Sift4G	Benign	0.89	T;T;T;T
Polyphen		0.093	B;.;B;B
Vest4		0.25
MPC		0.30
ClinPred		0.013	T
GERP RS		4.6
Varity_R		0.077
gMVP		0.44

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: rs3802829; hg19: chr11-101454192; COSMIC: COSV60252217; COSMIC: COSV60252217;