chr11-101473700-A-G

Variant names:

• chr11-101473700-A-G
• rs139187399
• NM_004621.6:c.1818T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004621.6(TRPC6):​c.1818T>C​(p.Ser606Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.000371 in 1,613,768 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: TRPC6 NM_004621.6 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 3.95
• Publications: 1 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 11-101473700-A-G is Benign according to our data. Variant chr11-101473700-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 259457.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00203 (309/152284) while in subpopulation AFR AF = 0.00727 (302/41564). AF 95% confidence interval is 0.00659. There are 0 homozygotes in GnomAd4. There are 148 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 309 AD gene.

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.1818T>C	p.Ser606Ser	synonymous	Exon 7 of 13	NP_004612.2
	TRPC6	NM_001439335.1		c.1470T>C	p.Ser490Ser	synonymous	Exon 5 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.1818T>C	p.Ser606Ser	synonymous	Exon 7 of 13	ENSP00000340913.3
	TRPC6	ENST00000360497.4	TSL:1	c.1653T>C	p.Ser551Ser	synonymous	Exon 6 of 12	ENSP00000353687.4
	TRPC6	ENST00000348423.8	TSL:1	c.1470T>C	p.Ser490Ser	synonymous	Exon 5 of 11	ENSP00000343672.4

Frequencies

GnomAD3 genomes AF: 0.00202 AC: 307 AN: 152166 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00721

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000443 AC: 111 AN: 250820 AF XY: 0.000310

Gnomad AFR exome AF: 0.00659

Gnomad AMR exome AF: 0.0000579

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000198 AC: 289 AN: 1461484 Hom.: 0 Cov.: 32 AF XY: 0.000168 AC XY: 122 AN XY: 727040

African (AFR) AF: 0.00718 AC: 240 AN: 33448

American (AMR) AF: 0.000179 AC: 8 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39640

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1111762

Other (OTH) AF: 0.000613 AC: 37 AN: 60370

GnomAD4 genome AF: 0.00203 AC: 309 AN: 152284 Hom.: 0 Cov.: 32 AF XY: 0.00199 AC XY: 148 AN XY: 74466

African (AFR) AF: 0.00727 AC: 302 AN: 41564

American (AMR) AF: 0.000262 AC: 4 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.00142 AC: 3 AN: 2112

Alfa AF: 0.00116 Hom.: 0

Bravo AF: 0.00214

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Focal segmental glomerulosclerosis 2 (2)
-	-	2	not provided (2)
-	-	1	not specified (1)
-	-	1	TRPC6-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
CADD	Benign	9.8
DANN	Benign	0.71
PhyloP100		3.9
Mutation Taster		=98/2	polymorphism

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: rs139187399; hg19: chr11-101344431;