rs56134796

Positions:

• chr11-101583721-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000344327.8(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 ENST00000344327.8 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.325

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]

ACMG classification

Verdict is Benign. Variant got -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 id 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/exons	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.-218C>T		5_prime_UTR_variant	1/13	ENST00000344327.8	NP_004612.2
TRPC6	XM_017018221.3	c.-218C>T		5_prime_UTR_variant	1/11		XP_016873710.1
TRPC6	XM_047427510.1	c.-218C>T		5_prime_UTR_variant	1/11		XP_047283466.1
TRPC6	XM_047427509.1	c.-89+211C>T		intron_variant			XP_047283465.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.-218C>T		5_prime_UTR_variant	1/13	1	NM_004621.6	ENSP00000340913	P1
TRPC6	ENST00000526713.1	n.266-78923C>T		intron_variant, non_coding_transcript_variant		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

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.157

Gnomad4 ASJ exome AF: 0.268

Gnomad4 EAS exome AF: 0.000128

Gnomad4 SAS exome AF: 0.112

Gnomad4 FIN exome AF: 0.254

Gnomad4 NFE exome AF: 0.247

Gnomad4 OTH exome AF: 0.212

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

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.171

Gnomad4 ASJ AF: 0.274

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.123

Gnomad4 FIN AF: 0.275

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.217

Alfa AF: 0.217 Hom.: 701

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

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 20, 2019	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Focal segmental glomerulosclerosis 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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

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

Publications

LitVar

Other links and lift over

dbSNP: rs56134796; hg19: chr11-101454452;