rs12805398

Variant names:

• chr11-101453039-C-T
• rs12805398
• NM_004621.6:c.2712G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_004621.6(TRPC6):​c.2712G>A​(p.Gln904Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 1,613,612 control chromosomes in the GnomAD database, including 12,329 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.090 (842 hom., cov: 32)
  • Exomes 𝑓: 0.12 (11487 hom.)
• Consequence: TRPC6 NM_004621.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0810
• Publications: 12 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 11-101453039-C-T is Benign according to our data. Variant chr11-101453039-C-T is described in ClinVar as Benign. ClinVar VariationId is 259462.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.081 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.127 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.2712G>A	p.Gln904Gln	synonymous	Exon 13 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.2364G>A	p.Gln788Gln	synonymous	Exon 11 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.2712G>A	p.Gln904Gln	synonymous	Exon 13 of 13	ENSP00000340913.3	Q9Y210-1
	TRPC6	ENST00000360497.4	TSL:1	c.2547G>A	p.Gln849Gln	synonymous	Exon 12 of 12	ENSP00000353687.4	Q9Y210-3
	TRPC6	ENST00000348423.8	TSL:1	c.2364G>A	p.Gln788Gln	synonymous	Exon 11 of 11	ENSP00000343672.4	Q9Y210-2

Frequencies

GnomAD3 genomes AF: 0.0901 AC: 13702 AN: 152096 Hom.: 840 Cov.: 32

Gnomad AFR AF: 0.0259

Gnomad AMI AF: 0.0910

Gnomad AMR AF: 0.0750

Gnomad ASJ AF: 0.142

Gnomad EAS AF: 0.0633

Gnomad SAS AF: 0.0978

Gnomad FIN AF: 0.0998

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.129

Gnomad OTH AF: 0.105

GnomAD2 exomes AF: 0.104 AC: 26050 AN: 251026 AF XY: 0.109

Gnomad AFR exome AF: 0.0234

Gnomad AMR exome AF: 0.0562

Gnomad ASJ exome AF: 0.148

Gnomad EAS exome AF: 0.0521

Gnomad FIN exome AF: 0.100

Gnomad NFE exome AF: 0.132

Gnomad OTH exome AF: 0.111

GnomAD4 exome AF: 0.122 AC: 178699 AN: 1461398 Hom.: 11487 Cov.: 32 AF XY: 0.123 AC XY: 89468 AN XY: 726996

African (AFR) AF: 0.0239 AC: 801 AN: 33466

American (AMR) AF: 0.0610 AC: 2725 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.145 AC: 3792 AN: 26114

East Asian (EAS) AF: 0.116 AC: 4592 AN: 39672

South Asian (SAS) AF: 0.114 AC: 9822 AN: 86248

European-Finnish (FIN) AF: 0.103 AC: 5509 AN: 53392

Middle Eastern (MID) AF: 0.149 AC: 861 AN: 5764

European-Non Finnish (NFE) AF: 0.129 AC: 143405 AN: 1111666

Other (OTH) AF: 0.119 AC: 7192 AN: 60374

GnomAD4 genome AF: 0.0900 AC: 13699 AN: 152214 Hom.: 842 Cov.: 32 AF XY: 0.0891 AC XY: 6631 AN XY: 74416

African (AFR) AF: 0.0260 AC: 1079 AN: 41564

American (AMR) AF: 0.0749 AC: 1145 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.142 AC: 491 AN: 3468

East Asian (EAS) AF: 0.0629 AC: 324 AN: 5152

South Asian (SAS) AF: 0.0981 AC: 473 AN: 4820

European-Finnish (FIN) AF: 0.0998 AC: 1058 AN: 10600

Middle Eastern (MID) AF: 0.177 AC: 52 AN: 294

European-Non Finnish (NFE) AF: 0.129 AC: 8773 AN: 68000

Other (OTH) AF: 0.105 AC: 221 AN: 2112

Alfa AF: 0.117 Hom.: 549

Bravo AF: 0.0846

Asia WGS AF: 0.0680 AC: 237 AN: 3478

EpiCase AF: 0.135

EpiControl AF: 0.133

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	2	not specified (2)
-	-	1	Focal segmental glomerulosclerosis 2 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
CADD	Benign	6.1
DANN	Benign	0.55
PhyloP100		-0.081
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

Other links and lift over

dbSNP: rs12805398; hg19: chr11-101323770; COSMIC: COSV60254838; COSMIC: COSV60254838;