rs56134796

Variant names:

• chr11-101583721-G-A
• rs56134796
• NM_004621.6:c.-218C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-101583721-G-A
• chr11-101583721-G-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_004621.6(TRPC6):​c.-218C>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.211 in 472,656 control chromosomes in the GnomAD database, including 12,183 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3537 hom., cov: 33)
  • Exomes 𝑓: 0.22 (8646 hom.)
• Consequence: TRPC6 NM_004621.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.325
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.75).
• BP6: Variant 11-101583721-G-A is Benign according to our data. Variant chr11-101583721-G-A is described in ClinVar as Benign. ClinVar VariationId is 301918.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.253 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.-218C>T		5_prime_UTR_variant	Exon 1 of 13	ENST00000344327.8	NP_004612.2
TRPC6	NM_001439335.1	c.-218C>T		5_prime_UTR_variant	Exon 1 of 11		NP_001426264.1
TRPC6	XM_047427510.1	c.-218C>T		5_prime_UTR_variant	Exon 1 of 11		XP_047283466.1
TRPC6	XM_047427509.1	c.-89+211C>T		intron_variant	Intron 1 of 12		XP_047283465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.-218C>T		5_prime_UTR_variant	Exon 1 of 13	1	NM_004621.6	ENSP00000340913.3

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30391 AN: 152076 Hom.: 3538 Cov.: 33

Gnomad AFR AF: 0.119

Gnomad AMI AF: 0.466

Gnomad AMR AF: 0.171

Gnomad ASJ AF: 0.274

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.275

Gnomad MID AF: 0.351

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.220

GnomAD4 exome AF: 0.216 AC: 69338 AN: 320462 Hom.: 8646 Cov.: 4 AF XY: 0.216 AC XY: 35448 AN XY: 164182

African (AFR) AF: 0.122 AC: 926 AN: 7614

American (AMR) AF: 0.157 AC: 1346 AN: 8600

Ashkenazi Jewish (ASJ) AF: 0.268 AC: 2779 AN: 10380

East Asian (EAS) AF: 0.000128 AC: 3 AN: 23514

South Asian (SAS) AF: 0.112 AC: 1668 AN: 14868

European-Finnish (FIN) AF: 0.254 AC: 6269 AN: 24654

Middle Eastern (MID) AF: 0.306 AC: 461 AN: 1508

European-Non Finnish (NFE) AF: 0.247 AC: 51740 AN: 209744

Other (OTH) AF: 0.212 AC: 4146 AN: 19580

GnomAD4 genome AF: 0.200 AC: 30380 AN: 152194 Hom.: 3537 Cov.: 33 AF XY: 0.199 AC XY: 14795 AN XY: 74426

African (AFR) AF: 0.118 AC: 4916 AN: 41542

American (AMR) AF: 0.171 AC: 2611 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.274 AC: 950 AN: 3468

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5156

South Asian (SAS) AF: 0.123 AC: 596 AN: 4828

European-Finnish (FIN) AF: 0.275 AC: 2921 AN: 10606

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.256 AC: 17395 AN: 67974

Other (OTH) AF: 0.217 AC: 458 AN: 2112

Alfa AF: 0.215 Hom.: 708

Bravo AF: 0.191

Asia WGS AF: 0.0610 AC: 213 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 2 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.75
CADD	Benign	8.3
DANN	Benign	0.87
PhyloP100		0.33
PromoterAI		-0.034	Neutral
Mutation Taster		=298/2	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: rs56134796; hg19: chr11-101454452;