NM_004621.6:c.171-20A>G

Variant names:

• chr11-101504818-T-C
• rs10501986
• NM_004621.6:c.171-20A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_004621.6(TRPC6):​c.171-20A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.438 in 1,608,228 control chromosomes in the GnomAD database, including 157,253 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16365 hom., cov: 32)
  • Exomes 𝑓: 0.44 (140888 hom.)
• Consequence: TRPC6 NM_004621.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.0830
• Publications: 11 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 -16 ACMG points.

• BP6: Variant 11-101504818-T-C is Benign according to our data. Variant chr11-101504818-T-C is described in ClinVar as Benign. ClinVar VariationId is 259456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.539 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.171-20A>G		intron	N/A	NP_004612.2
	TRPC6	NM_001439335.1		c.171-20A>G		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.171-20A>G		intron	N/A	ENSP00000340913.3
	TRPC6	ENST00000360497.4	TSL:1	c.171-20A>G		intron	N/A	ENSP00000353687.4
	TRPC6	ENST00000348423.8	TSL:1	c.171-20A>G		intron	N/A	ENSP00000343672.4

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69695 AN: 151916 Hom.: 16348 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.396

Gnomad ASJ AF: 0.463

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.373

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.442

GnomAD2 exomes AF: 0.409 AC: 99636 AN: 243324 AF XY: 0.410

Gnomad AFR exome AF: 0.551

Gnomad AMR exome AF: 0.349

Gnomad ASJ exome AF: 0.439

Gnomad EAS exome AF: 0.180

Gnomad FIN exome AF: 0.426

Gnomad NFE exome AF: 0.449

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.436 AC: 634767 AN: 1456194 Hom.: 140888 Cov.: 43 AF XY: 0.434 AC XY: 314619 AN XY: 724200

African (AFR) AF: 0.559 AC: 18541 AN: 33192

American (AMR) AF: 0.358 AC: 15592 AN: 43564

Ashkenazi Jewish (ASJ) AF: 0.440 AC: 11315 AN: 25708

East Asian (EAS) AF: 0.214 AC: 8484 AN: 39662

South Asian (SAS) AF: 0.380 AC: 32539 AN: 85552

European-Finnish (FIN) AF: 0.428 AC: 22741 AN: 53190

Middle Eastern (MID) AF: 0.466 AC: 2652 AN: 5690

European-Non Finnish (NFE) AF: 0.448 AC: 496903 AN: 1109504

Other (OTH) AF: 0.432 AC: 26000 AN: 60132

GnomAD4 genome AF: 0.459 AC: 69772 AN: 152034 Hom.: 16365 Cov.: 32 AF XY: 0.455 AC XY: 33810 AN XY: 74306

African (AFR) AF: 0.545 AC: 22608 AN: 41462

American (AMR) AF: 0.396 AC: 6046 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.463 AC: 1606 AN: 3466

East Asian (EAS) AF: 0.189 AC: 977 AN: 5174

South Asian (SAS) AF: 0.375 AC: 1805 AN: 4818

European-Finnish (FIN) AF: 0.439 AC: 4642 AN: 10566

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.450 AC: 30577 AN: 67954

Other (OTH) AF: 0.444 AC: 936 AN: 2108

Alfa AF: 0.451 Hom.: 60313

Bravo AF: 0.460

Asia WGS AF: 0.311 AC: 1083 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Uncertain	23
DANN	Benign	0.76
PhyloP100		-0.083
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.45		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.45		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10501986; hg19: chr11-101375549; COSMIC: COSV60250929; COSMIC: COSV60250929;