rs121434390

Positions:

• chr11-101504634-G-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.335C>A​(p.Pro112Gln) 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 Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P112S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 10.0

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 hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_004621.6
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.923
• PP5: Variant 11-101504634-G-T is Pathogenic according to our data. Variant chr11-101504634-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 6151.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.335C>A	p.Pro112Gln	missense_variant	2/13	ENST00000344327.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8	c.335C>A	p.Pro112Gln	missense_variant	2/13	1	NM_004621.6	P1
TRPC6	ENST00000360497.4	c.335C>A	p.Pro112Gln	missense_variant	2/12	1
TRPC6	ENST00000348423.8	c.335C>A	p.Pro112Gln	missense_variant	2/11	1
TRPC6	ENST00000532133.5	c.335C>A	p.Pro112Gln	missense_variant	2/12	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Focal segmental glomerulosclerosis 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	Jul 17, 2023	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0101 - Gain of function is a known mechanism of disease in this gene and is associated with glomerulosclerosis, focal segmental, 2 (MIM#603965). Missense variants have been functionally proven to result in increased calcium channel activity (PMID: 15879175, PMID: 32509715). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from proline to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0600 - Variant is located in the annotated ankyrin repeat domain (DECIPHER). (I) 0703 - Other missense variants comparable to the one identified in this case have moderate previous evidence for pathogenicity. One alternative change (p.(Pro112Arg)) was observed as de novo in an individual with sub-nephrotic range proteinuria (PMID: 32509715), and another alternative change (p.(Pro112Leu)) has been reported in an individual with focal segmental glomerulosclerosis (FSGS) and proteinuria, who also had a non-pathogenic variant in the COL4A5 gene (PMID: 31576025). (SP) 0803 - This variant has limited previous evidence of pathogenicity in an unrelated individual. This variant has been reported in a single family with FSGS (PMID: 15879175). (SP) 0901 - This variant has strong evidence for segregation with disease. This variant segregated in 20 affected individuals within a single family with FSGS (PMID: 15879175). (SP) 1002 - This variant has moderate functional evidence supporting abnormal protein function. Transfected cells showed increased intracellular calcium, increased angiotensin signalling and protein mislocalization (PMID: 15879175). (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 17, 2005	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.25
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.42	T;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.76
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.92	D;D;D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.55	N;.;N;N
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.0	D;D;D;D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.81
MutPred		0.80		Loss of catalytic residue at P112 (P = 0.096);Loss of catalytic residue at P112 (P = 0.096);Loss of catalytic residue at P112 (P = 0.096);Loss of catalytic residue at P112 (P = 0.096);
MVP		0.86
MPC		0.98
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.88
gMVP		0.55

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: rs121434390; hg19: chr11-101375365;