chr11-101504326-G-C

Position:

• chr11-101504326-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 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).

• 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

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.873

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.643C>G	p.Arg215Gly	missense_variant	2/13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.643C>G	p.Arg215Gly	missense_variant	2/13	1	NM_004621.6	ENSP00000340913.3
TRPC6	ENST00000360497.4	c.643C>G	p.Arg215Gly	missense_variant	2/12	1		ENSP00000353687.4
TRPC6	ENST00000348423.8	c.643C>G	p.Arg215Gly	missense_variant	2/11	1		ENSP00000343672.4
TRPC6	ENST00000532133.5	c.643C>G	p.Arg215Gly	missense_variant	2/12	5		ENSP00000435574.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Focal segmental glomerulosclerosis 2 Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare

May 09, 2023

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Computational scores

Source: dbNSFP v4.3

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;D;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.87	D;D;D;D
MetaSVM	Uncertain	0.39	D
MutationAssessor	Pathogenic	2.9	M;.;M;M
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-4.1	D;D;D;D
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0090	D;D;D;D
Sift4G	Uncertain	0.018	D;D;D;D
Polyphen		1.0	D;.;D;D
Vest4		0.92
MutPred		0.47		Gain of catalytic residue at S217 (P = 0.0379);Gain of catalytic residue at S217 (P = 0.0379);Gain of catalytic residue at S217 (P = 0.0379);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

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: rs768210838; hg19: chr11-101375057;