chr11-101472227-G-A

Variant names:

• chr11-101472227-G-A
• rs61743044
• NM_004621.6:c.2115C>T

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.2115C>T​(p.Tyr705Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0235 in 1,612,978 control chromosomes in the GnomAD database, including 727 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.041 (248 hom., cov: 32)
  • Exomes 𝑓: 0.022 (479 hom.)
• Consequence: TRPC6 NM_004621.6 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.453
• 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: 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=-0.5).
• BP6: Variant 11-101472227-G-A is Benign according to our data. Variant chr11-101472227-G-A is described in ClinVar as Benign. ClinVar VariationId is 259458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.453 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0997 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.2115C>T	p.Tyr705Tyr	synonymous	Exon 8 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.1767C>T	p.Tyr589Tyr	synonymous	Exon 6 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.2115C>T	p.Tyr705Tyr	synonymous	Exon 8 of 13	ENSP00000340913.3
	TRPC6	ENST00000360497.4	TSL:1	c.1950C>T	p.Tyr650Tyr	synonymous	Exon 7 of 12	ENSP00000353687.4
	TRPC6	ENST00000348423.8	TSL:1	c.1767C>T	p.Tyr589Tyr	synonymous	Exon 6 of 11	ENSP00000343672.4

Frequencies

GnomAD3 genomes AF: 0.0411 AC: 6245 AN: 152062 Hom.: 248 Cov.: 32

Gnomad AFR AF: 0.102

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0183

Gnomad ASJ AF: 0.0265

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00559

Gnomad FIN AF: 0.00624

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0218

Gnomad OTH AF: 0.0296

GnomAD2 exomes AF: 0.0200 AC: 4996 AN: 250108 AF XY: 0.0182

Gnomad AFR exome AF: 0.107

Gnomad AMR exome AF: 0.00988

Gnomad ASJ exome AF: 0.0219

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00755

Gnomad NFE exome AF: 0.0196

Gnomad OTH exome AF: 0.0219

GnomAD4 exome AF: 0.0216 AC: 31622 AN: 1460798 Hom.: 479 Cov.: 31 AF XY: 0.0208 AC XY: 15110 AN XY: 726706

African (AFR) AF: 0.109 AC: 3634 AN: 33436

American (AMR) AF: 0.0107 AC: 479 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0247 AC: 645 AN: 26088

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39654

South Asian (SAS) AF: 0.00695 AC: 599 AN: 86146

European-Finnish (FIN) AF: 0.00852 AC: 454 AN: 53294

Middle Eastern (MID) AF: 0.0288 AC: 164 AN: 5694

European-Non Finnish (NFE) AF: 0.0217 AC: 24124 AN: 1111446

Other (OTH) AF: 0.0252 AC: 1522 AN: 60340

GnomAD4 genome AF: 0.0411 AC: 6258 AN: 152180 Hom.: 248 Cov.: 32 AF XY: 0.0388 AC XY: 2886 AN XY: 74384

African (AFR) AF: 0.102 AC: 4243 AN: 41502

American (AMR) AF: 0.0183 AC: 279 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0265 AC: 92 AN: 3470

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.00580 AC: 28 AN: 4824

European-Finnish (FIN) AF: 0.00624 AC: 66 AN: 10578

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.0218 AC: 1480 AN: 68014

Other (OTH) AF: 0.0293 AC: 62 AN: 2114

Alfa AF: 0.0312 Hom.: 73

Bravo AF: 0.0444

Asia WGS AF: 0.00866 AC: 30 AN: 3478

EpiCase AF: 0.0198

EpiControl AF: 0.0191

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Focal segmental glomerulosclerosis 2 (2)
-	-	1	Focal segmental glomerulosclerosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.50
CADD	Benign	2.4
DANN	Benign	0.47
PhyloP100		0.45
Mutation Taster		=89/11	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs61743044; hg19: chr11-101342958; COSMIC: COSV60252389;