11-101583475-C-T

Variant names:

• chr11-101583475-C-T
• rs1227678536
• NM_004621.6:c.29G>A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS2_Supporting

The NM_004621.6(TRPC6):​c.29G>A​(p.Arg10Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000367 in 1,363,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000037 (0 hom.)
• Consequence: TRPC6 NM_004621.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.80

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25315732).
• BS2: High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.29G>A	p.Arg10Gln	missense_variant	Exon 1 of 13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.29G>A	p.Arg10Gln	missense_variant	Exon 1 of 13	1	NM_004621.6	ENSP00000340913.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000367 AC: 5 AN: 1363642 Hom.: 0 Cov.: 31 AF XY: 0.00000448 AC XY: 3 AN XY: 669130

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000597

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000282

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 10, 2017

Athena Diagnostics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Benign	0.21	T;.;.;.
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.095
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Uncertain	0.23	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.55	N;.;N;N
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.41	N;N;N;N
REVEL	Uncertain	0.31
Sift	Uncertain	0.016	D;D;D;D
Sift4G	Benign	0.25	T;T;T;T
Polyphen		0.21	B;.;B;B
Vest4		0.25
MutPred		0.30		Loss of MoRF binding (P = 0.0105);Loss of MoRF binding (P = 0.0105);Loss of MoRF binding (P = 0.0105);Loss of MoRF binding (P = 0.0105);
MVP		0.78
MPC		0.34
ClinPred		0.34	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.41

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: rs1227678536; hg19: chr11-101454206;