rs121434392

chr11-101504161-A-T

Variant summary

Our verdict is Likely pathogenic. Variant got 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

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 Likely_pathogenic. Variant got 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 id is 6153.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC6	NM_004621.6	c.808T>A	p.Ser270Thr	missense_variant	2/13	ENST00000344327.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC6	ENST00000344327.8	c.808T>A	p.Ser270Thr	missense_variant	2/13	1	NM_004621.6	P1
TRPC6	ENST00000360497.4	c.808T>A	p.Ser270Thr	missense_variant	2/12	1
TRPC6	ENST00000348423.8	c.808T>A	p.Ser270Thr	missense_variant	2/11	1
TRPC6	ENST00000532133.5	c.808T>A	p.Ser270Thr	missense_variant	2/12	5

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

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;D;D;D
M_CAP	Uncertain	0.25	D
MetaRNN	Pathogenic	0.97	D;D;D;D
MetaSVM	Uncertain	0.73	D
MutationAssessor	Uncertain	2.7	M;.;M;M
MutationTaster	Benign	1.0	A;A;A;A
PrimateAI	Uncertain	0.76	T
PROVEAN	Uncertain	-2.6	D;D;N;D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0020	D;D;D;D
Sift4G	Uncertain	0.045	D;D;D;T
Polyphen		1.0	D;.;D;D
Vest4		0.76
MutPred		0.92		Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);Loss of disorder (P = 0.0617);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

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: rs121434392; hg19: chr11-101374892;