chr11-101453062-C-T

Variant names:

• chr11-101453062-C-T
• rs121434395
• NM_004621.6:c.2689G>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.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 (★). ClinVar reports functional evidence for this variant: "SCV004084527: Functional studies show that E897K leads to altered protein function (Reiser, 2005" and additional evidence is available in ClinVar.

• 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
• Publications: 33 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: SCV004084527: Functional studies show that E897K leads to altered protein function (Reiser, 2005; Riehle, 2016; Polat, 2019; Schlöndorff, 2009).
• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain 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 VariationId is 6156.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.2689G>A	p.Glu897Lys	missense	Exon 13 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.2341G>A	p.Glu781Lys	missense	Exon 11 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.2689G>A	p.Glu897Lys	missense	Exon 13 of 13	ENSP00000340913.3	Q9Y210-1
	TRPC6	ENST00000360497.4	TSL:1	c.2524G>A	p.Glu842Lys	missense	Exon 12 of 12	ENSP00000353687.4	Q9Y210-3
	TRPC6	ENST00000348423.8	TSL:1	c.2341G>A	p.Glu781Lys	missense	Exon 11 of 11	ENSP00000343672.4	Q9Y210-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.000548 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Focal segmental glomerulosclerosis 2 (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.89	D
MetaSVM	Uncertain	0.67	D
MutationAssessor	Pathogenic	3.1	M
PhyloP100		7.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	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
Mutation Taster		=0/100	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: rs121434395; hg19: chr11-101323793;