rs121434390

Variant names:

• chr11-101504634-G-T
• rs121434390
• NM_004621.6:c.335C>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS3 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 (★). ClinVar reports functional evidence for this variant: "SCV005087202: "Missense variants have been functionally proven to result in increased calcium channel activity (PMID:15879175, PMID:32509715)." "Transfected cells showed increased intracellular calcium, increased angiotensin signalling and protein mislocalization (PMID:15879175)."". 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
• Publications: 41 publications found

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]

TRPC6 Gene-Disease associations (from GenCC):

• focal segmental glomerulosclerosis 2

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005087202: "Missense variants have been functionally proven to result in increased calcium channel activity (PMID: 15879175, PMID: 32509715)." "Transfected cells showed increased intracellular calcium, increased angiotensin signalling and protein mislocalization (PMID: 15879175)."
• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 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 VariationId is 6151.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004621.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	NM_004621.6	MANE Select	c.335C>A	p.Pro112Gln	missense	Exon 2 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.335C>A	p.Pro112Gln	missense	Exon 2 of 11	NP_001426264.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	ENST00000344327.8	TSL:1 MANE Select	c.335C>A	p.Pro112Gln	missense	Exon 2 of 13	ENSP00000340913.3	Q9Y210-1
	TRPC6	ENST00000360497.4	TSL:1	c.335C>A	p.Pro112Gln	missense	Exon 2 of 12	ENSP00000353687.4	Q9Y210-3
	TRPC6	ENST00000348423.8	TSL:1	c.335C>A	p.Pro112Gln	missense	Exon 2 of 11	ENSP00000343672.4	Q9Y210-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
2	-	-	Focal segmental glomerulosclerosis 2 (2)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Benign	0.034	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Benign	0.55	N
PhyloP100		10
PrimateAI	Uncertain	0.66	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.66
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.80		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
Mutation Taster		=1/99	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121434390; hg19: chr11-101375365;