rs121434395

chr11-101453062-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_004621.6(TRPC6):c.2689G>A(p.Glu897Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:3
• Conservation: PhyloP100: 7.71

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 Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a helix (size 36) in uniprot entity TRPC6_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_004621.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.894
• PP5: Variant 11-101453062-C-T is Pathogenic according to our data. Variant chr11-101453062-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 6156.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC6	NM_004621.6	c.2689G>A	p.Glu897Lys	missense_variant	13/13	ENST00000344327.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8	c.2689G>A	p.Glu897Lys	missense_variant	13/13	1	NM_004621.6	P1
TRPC6	ENST00000360497.4	c.2524G>A	p.Glu842Lys	missense_variant	12/12	1
TRPC6	ENST00000348423.8	c.2341G>A	p.Glu781Lys	missense_variant	11/11	1
TRPC6	ENST00000532133.5	c.2455G>A	p.Glu819Lys	missense_variant	12/12	5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.00209 Hom.: 0

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 21, 2023

The c.2689G>A (p.E897K) alteration is located in exon 13 (coding exon 13) of the TRPC6 gene. This alteration results from a G to A substitution at nucleotide position 2689, causing the glutamic acid (E) at amino acid position 897 to be replaced by a lysine (K). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been identified in multiple individuals with clinical features consistent with TRPC6-related focal segmental glomerulosclerosis (Reiser, 2005; Groopman, 2019; Lu, 2022). This amino acid position is highly conserved in available vertebrate species. Based on internal structural analysis, E897K is more disruptive to the CH2 domain of TRPC6 than our internal threshold for deleterious destabilization, though there are no comparable internally pathogenic variants nearby for comparison (Tang, 2018; Guo, 2022). Functional studies show that E897K leads to altered protein function (Reiser, 2005; Riehle, 2016; Polat, 2019; Schlöndorff, 2009). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as likely pathogenic. -

not provided Pathogenic:1

Pathogenic, no assertion criteria provided

research

Gharavi Laboratory, Columbia University

Sep 16, 2018

- -

Focal segmental glomerulosclerosis 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
DEOGEN2	Pathogenic	0.83	D;.;.;.
Eigen	Pathogenic	0.86
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D;D;D;D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.1	M;.;.;.
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D;D;D;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D;D;D;D
Sift4G	Uncertain	0.0040	D;D;D;D
Polyphen		1.0	D;.;D;.
Vest4		0.90
MutPred		0.79		Gain of ubiquitination at E897 (P = 0.0101);.;.;.;
MVP		0.98
MPC		0.21
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.92
gMVP		0.82

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: rs121434395; hg19: chr11-101323793;