rs4129255

Variant names:

• chr11-101494472-G-A
• rs4129255
• NM_004621.6:c.946-2734C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004621.6(TRPC6):​c.946-2734C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.417 in 151,878 control chromosomes in the GnomAD database, including 14,009 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.42 (14009 hom., cov: 31)
• Consequence: TRPC6 NM_004621.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.140
• Publications: 5 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: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• familial idiopathic steroid-resistant nephrotic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.96).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.571 is higher than 0.05.

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.946-2734C>T		intron	N/A	NP_004612.2
	TRPC6	NM_001439335.1		c.945+9552C>T		intron	N/A	NP_001426264.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	ENST00000344327.8	TSL:1 MANE Select	c.946-2734C>T		intron	N/A	ENSP00000340913.3	Q9Y210-1
	TRPC6	ENST00000360497.4	TSL:1	c.946-2734C>T		intron	N/A	ENSP00000353687.4	Q9Y210-3
	TRPC6	ENST00000348423.8	TSL:1	c.945+9552C>T		intron	N/A	ENSP00000343672.4	Q9Y210-2

Frequencies

GnomAD3 genomes AF: 0.417 AC: 63242 AN: 151756 Hom.: 13976 Cov.: 31

Gnomad AFR AF: 0.576

Gnomad AMI AF: 0.377

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.188

Gnomad SAS AF: 0.344

Gnomad FIN AF: 0.367

Gnomad MID AF: 0.411

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.404

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.417 AC: 63340 AN: 151878 Hom.: 14009 Cov.: 31 AF XY: 0.413 AC XY: 30628 AN XY: 74232

African (AFR) AF: 0.577 AC: 23875 AN: 41396

American (AMR) AF: 0.352 AC: 5367 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1338 AN: 3466

East Asian (EAS) AF: 0.187 AC: 969 AN: 5178

South Asian (SAS) AF: 0.345 AC: 1658 AN: 4804

European-Finnish (FIN) AF: 0.367 AC: 3864 AN: 10538

Middle Eastern (MID) AF: 0.412 AC: 121 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24946 AN: 67924

Other (OTH) AF: 0.407 AC: 859 AN: 2112

Alfa AF: 0.379 Hom.: 6138

Bravo AF: 0.421

Asia WGS AF: 0.297 AC: 1035 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.96
CADD	Benign	1.1
DANN	Benign	0.60
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs4129255;

hg19: chr11-101365203;