11-101504326-G-C

Variant names:

• chr11-101504326-G-C
• rs768210838
• NM_004621.6:c.643C>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PM5 PP3_Moderate

The NM_004621.6(TRPC6):​c.643C>G​(p.Arg215Gly) variant causes a missense change. 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 Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R215W) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 5.75
• Publications: 3 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 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr11-101504326-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 562374.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

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.643C>G	p.Arg215Gly	missense	Exon 2 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.643C>G	p.Arg215Gly	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.643C>G	p.Arg215Gly	missense	Exon 2 of 13	ENSP00000340913.3	Q9Y210-1
	TRPC6	ENST00000360497.4	TSL:1	c.643C>G	p.Arg215Gly	missense	Exon 2 of 12	ENSP00000353687.4	Q9Y210-3
	TRPC6	ENST00000348423.8	TSL:1	c.643C>G	p.Arg215Gly	missense	Exon 2 of 11	ENSP00000343672.4	Q9Y210-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	1	-	Focal segmental glomerulosclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.63	D
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	2.9	M
PhyloP100		5.7
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.018	D
Polyphen		1.0	D
Vest4		0.92
MutPred		0.47		Gain of catalytic residue at S217 (P = 0.0379)
MVP		0.91
MPC		1.1
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.67
gMVP		0.81
Mutation Taster		=15/85	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: rs768210838; hg19: chr11-101375057;