NM_004621.6:c.1683T>C

Variant names:

• chr11-101476362-A-G
• rs12366144
• NM_004621.6:c.1683T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_004621.6(TRPC6):​c.1683T>C​(p.Asn561Asn) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.247 in 1,613,812 control chromosomes in the GnomAD database, including 53,748 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (8742 hom., cov: 32)
  • Exomes 𝑓: 0.24 (45006 hom.)
• Consequence: TRPC6 NM_004621.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 1.17
• Publications: 18 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-101476362-A-G is Benign according to our data. Variant chr11-101476362-A-G is described in ClinVar as Benign. ClinVar VariationId is 259455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.17 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.527 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	NM_004621.6	MANE Select	c.1683T>C	p.Asn561Asn	synonymous	Exon 6 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.1335T>C	p.Asn445Asn	synonymous	Exon 4 of 11	NP_001426264.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	ENST00000344327.8	TSL:1 MANE Select	c.1683T>C	p.Asn561Asn	synonymous	Exon 6 of 13	ENSP00000340913.3
	TRPC6	ENST00000360497.4	TSL:1	c.1518T>C	p.Asn506Asn	synonymous	Exon 5 of 12	ENSP00000353687.4
	TRPC6	ENST00000348423.8	TSL:1	c.1335T>C	p.Asn445Asn	synonymous	Exon 4 of 11	ENSP00000343672.4

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46699 AN: 151942 Hom.: 8718 Cov.: 32

Gnomad AFR AF: 0.533

Gnomad AMI AF: 0.200

Gnomad AMR AF: 0.199

Gnomad ASJ AF: 0.237

Gnomad EAS AF: 0.0586

Gnomad SAS AF: 0.244

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.241

Gnomad OTH AF: 0.291

GnomAD2 exomes AF: 0.228 AC: 57351 AN: 251284 AF XY: 0.230

Gnomad AFR exome AF: 0.545

Gnomad AMR exome AF: 0.131

Gnomad ASJ exome AF: 0.238

Gnomad EAS exome AF: 0.0455

Gnomad FIN exome AF: 0.194

Gnomad NFE exome AF: 0.239

Gnomad OTH exome AF: 0.234

GnomAD4 exome AF: 0.240 AC: 351065 AN: 1461752 Hom.: 45006 Cov.: 36 AF XY: 0.241 AC XY: 174894 AN XY: 727174

African (AFR) AF: 0.555 AC: 18586 AN: 33474

American (AMR) AF: 0.141 AC: 6311 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.229 AC: 5975 AN: 26132

East Asian (EAS) AF: 0.0971 AC: 3853 AN: 39696

South Asian (SAS) AF: 0.257 AC: 22145 AN: 86252

European-Finnish (FIN) AF: 0.201 AC: 10734 AN: 53414

Middle Eastern (MID) AF: 0.333 AC: 1919 AN: 5764

European-Non Finnish (NFE) AF: 0.239 AC: 266219 AN: 1111906

Other (OTH) AF: 0.254 AC: 15323 AN: 60392

GnomAD4 genome AF: 0.308 AC: 46775 AN: 152060 Hom.: 8742 Cov.: 32 AF XY: 0.301 AC XY: 22387 AN XY: 74314

African (AFR) AF: 0.533 AC: 22086 AN: 41432

American (AMR) AF: 0.198 AC: 3031 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.237 AC: 823 AN: 3472

East Asian (EAS) AF: 0.0583 AC: 302 AN: 5180

South Asian (SAS) AF: 0.244 AC: 1175 AN: 4818

European-Finnish (FIN) AF: 0.197 AC: 2083 AN: 10588

Middle Eastern (MID) AF: 0.327 AC: 96 AN: 294

European-Non Finnish (NFE) AF: 0.241 AC: 16373 AN: 67986

Other (OTH) AF: 0.296 AC: 624 AN: 2108

Alfa AF: 0.271 Hom.: 2986

Bravo AF: 0.314

Asia WGS AF: 0.186 AC: 648 AN: 3478

EpiCase AF: 0.247

EpiControl AF: 0.243

ClinVar

ClinVar submissions as Germline

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	-0.48
CADD	Benign	5.3
DANN	Benign	0.61
PhyloP100		1.2
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs12366144; hg19: chr11-101347093; COSMIC: COSV60255434;