rs121434392

Variant names:

• chr11-101504161-A-T
• rs121434392
• NM_004621.6:c.808T>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PP3_Strong PP5

The NM_004621.6(TRPC6):​c.808T>A​(p.Ser270Thr) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 18 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.969
• PP5: Variant 11-101504161-A-T is Pathogenic according to our data. Variant chr11-101504161-A-T is described in ClinVar as Pathogenic. ClinVar VariationId is 6153.Status of the report is no_assertion_criteria_provided, 0 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	NM_004621.6	MANE Select	c.808T>A	p.Ser270Thr	missense	Exon 2 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.808T>A	p.Ser270Thr	missense	Exon 2 of 11	NP_001426264.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	ENST00000344327.8	TSL:1 MANE Select	c.808T>A	p.Ser270Thr	missense	Exon 2 of 13	ENSP00000340913.3
	TRPC6	ENST00000360497.4	TSL:1	c.808T>A	p.Ser270Thr	missense	Exon 2 of 12	ENSP00000353687.4
	TRPC6	ENST00000348423.8	TSL:1	c.808T>A	p.Ser270Thr	missense	Exon 2 of 11	ENSP00000343672.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Focal segmental glomerulosclerosis 2 Pathogenic:1

Jul 01, 2005

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.045	D
Polyphen		1.0	D
Vest4		0.76
MutPred		0.92		Loss of disorder (P = 0.0617)
MVP		0.97
MPC		0.96
ClinPred		0.97	D
GERP RS		5.8
Varity_R		0.84
gMVP		0.78
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: rs121434392; hg19: chr11-101374892;