11-101504884-C-G

Variant names:

• chr11-101504884-C-G
• rs10501981
• NM_004621.6:c.171-86G>C

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004621.6(TRPC6):​c.171-86G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.437 in 1,473,998 control chromosomes in the GnomAD database, including 143,332 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16345 hom., cov: 32)
  • Exomes 𝑓: 0.43 (126987 hom.)
• Consequence: TRPC6 NM_004621.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.119
• Publications: 6 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-101504884-C-G is Benign according to our data. Variant chr11-101504884-C-G is described in ClinVar as Benign. ClinVar VariationId is 1261382.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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.171-86G>C		intron_variant	Intron 1 of 12	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.171-86G>C		intron_variant	Intron 1 of 12	1	NM_004621.6	ENSP00000340913.3

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69644 AN: 151888 Hom.: 16328 Cov.: 32

Gnomad AFR AF: 0.545

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.189

Gnomad SAS AF: 0.368

Gnomad FIN AF: 0.441

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.443

GnomAD4 exome AF: 0.435 AC: 574737 AN: 1321994 Hom.: 126987 AF XY: 0.432 AC XY: 283576 AN XY: 656090

African (AFR) AF: 0.556 AC: 16600 AN: 29830

American (AMR) AF: 0.349 AC: 12121 AN: 34770

Ashkenazi Jewish (ASJ) AF: 0.429 AC: 9319 AN: 21704

East Asian (EAS) AF: 0.215 AC: 8274 AN: 38522

South Asian (SAS) AF: 0.370 AC: 27893 AN: 75436

European-Finnish (FIN) AF: 0.427 AC: 20836 AN: 48852

Middle Eastern (MID) AF: 0.475 AC: 1957 AN: 4116

European-Non Finnish (NFE) AF: 0.448 AC: 454061 AN: 1013828

Other (OTH) AF: 0.431 AC: 23676 AN: 54936

GnomAD4 genome AF: 0.459 AC: 69720 AN: 152004 Hom.: 16345 Cov.: 32 AF XY: 0.455 AC XY: 33789 AN XY: 74272

African (AFR) AF: 0.545 AC: 22583 AN: 41450

American (AMR) AF: 0.395 AC: 6044 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.464 AC: 1607 AN: 3464

East Asian (EAS) AF: 0.188 AC: 974 AN: 5168

South Asian (SAS) AF: 0.369 AC: 1781 AN: 4822

European-Finnish (FIN) AF: 0.441 AC: 4645 AN: 10536

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

European-Non Finnish (NFE) AF: 0.450 AC: 30573 AN: 67968

Other (OTH) AF: 0.445 AC: 938 AN: 2110

Alfa AF: 0.255 Hom.: 451

Bravo AF: 0.460

Asia WGS AF: 0.307 AC: 1067 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

not specified Benign:1

Jul 15, 2024

Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Benign based on local population frequency. This variant was detected in 48% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 45. Only high quality variants are reported. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.74
PhyloP100		0.12
Mutation Taster		=100/0	polymorphism (auto)

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: rs10501981; hg19: chr11-101375615; COSMIC: COSV60256815; COSMIC: COSV60256815;