chr11-101453125-TAAG-T

Variant names:

• chr11-101453125-TAAG-T
• rs59743346
• NM_004621.6:c.2645-22_2645-20delCTT

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.2645-22_2645-20delCTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.237 in 1,609,060 control chromosomes in the GnomAD database, including 51,845 homozygotes. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.31 (9656 hom., cov: 0)
  • Exomes 𝑓: 0.23 (42189 hom.)
• Consequence: TRPC6 NM_004621.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.640
• Publications: 2 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 11-101453125-TAAG-T is Benign according to our data. Variant chr11-101453125-TAAG-T is described in ClinVar as Benign. ClinVar VariationId is 259461.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.58 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.2645-22_2645-20delCTT		intron	N/A	NP_004612.2
	TRPC6	NM_001439335.1		c.2297-22_2297-20delCTT		intron	N/A	NP_001426264.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC6	ENST00000344327.8	TSL:1 MANE Select	c.2645-22_2645-20delCTT		intron	N/A	ENSP00000340913.3
	TRPC6	ENST00000360497.4	TSL:1	c.2480-22_2480-20delCTT		intron	N/A	ENSP00000353687.4
	TRPC6	ENST00000348423.8	TSL:1	c.2297-22_2297-20delCTT		intron	N/A	ENSP00000343672.4

Frequencies

GnomAD3 genomes AF: 0.312 AC: 47358 AN: 151728 Hom.: 9618 Cov.: 0

Gnomad AFR AF: 0.586

Gnomad AMI AF: 0.193

Gnomad AMR AF: 0.196

Gnomad ASJ AF: 0.259

Gnomad EAS AF: 0.0646

Gnomad SAS AF: 0.226

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.364

Gnomad NFE AF: 0.227

Gnomad OTH AF: 0.302

GnomAD2 exomes AF: 0.222 AC: 55406 AN: 250076 AF XY: 0.222

Gnomad AFR exome AF: 0.594

Gnomad AMR exome AF: 0.129

Gnomad ASJ exome AF: 0.268

Gnomad EAS exome AF: 0.0529

Gnomad FIN exome AF: 0.150

Gnomad NFE exome AF: 0.226

Gnomad OTH exome AF: 0.231

GnomAD4 exome AF: 0.229 AC: 333812 AN: 1457214 Hom.: 42189 AF XY: 0.229 AC XY: 166351 AN XY: 725118

African (AFR) AF: 0.611 AC: 20365 AN: 33334

American (AMR) AF: 0.141 AC: 6282 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.258 AC: 6729 AN: 26088

East Asian (EAS) AF: 0.116 AC: 4619 AN: 39656

South Asian (SAS) AF: 0.244 AC: 20982 AN: 86166

European-Finnish (FIN) AF: 0.156 AC: 8254 AN: 53034

Middle Eastern (MID) AF: 0.359 AC: 2069 AN: 5758

European-Non Finnish (NFE) AF: 0.225 AC: 249620 AN: 1108278

Other (OTH) AF: 0.247 AC: 14892 AN: 60216

GnomAD4 genome AF: 0.312 AC: 47451 AN: 151846 Hom.: 9656 Cov.: 0 AF XY: 0.304 AC XY: 22588 AN XY: 74188

African (AFR) AF: 0.586 AC: 24220 AN: 41304

American (AMR) AF: 0.196 AC: 2991 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.259 AC: 897 AN: 3466

East Asian (EAS) AF: 0.0641 AC: 331 AN: 5162

South Asian (SAS) AF: 0.226 AC: 1088 AN: 4808

European-Finnish (FIN) AF: 0.150 AC: 1583 AN: 10588

Middle Eastern (MID) AF: 0.371 AC: 109 AN: 294

European-Non Finnish (NFE) AF: 0.227 AC: 15406 AN: 67956

Other (OTH) AF: 0.308 AC: 650 AN: 2110

Alfa AF: 0.272 Hom.: 1253

Bravo AF: 0.326

Asia WGS AF: 0.189 AC: 659 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.64
BranchPoint Hunter		4.0
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs59743346; hg19: chr11-101323856;