11-101583757-G-C

Variant names:

• chr11-101583757-G-C
• rs3824934
• NM_004621.6:c.-254C>G

Variant summary

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

The NM_004621.6(TRPC6):​c.-254C>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 394,526 control chromosomes in the GnomAD database, including 4,279 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.098 (1292 hom., cov: 33)
  • Exomes 𝑓: 0.12 (2987 hom.)
• Consequence: TRPC6 NM_004621.6 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.330

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=-0.78).
• BP6: Variant 11-101583757-G-C is Benign according to our data. Variant chr11-101583757-G-C is described in ClinVar as [Benign]. Clinvar id is 301920.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.448 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.-254C>G		5_prime_UTR_variant	Exon 1 of 13	ENST00000344327.8	NP_004612.2
TRPC6	XM_047427510.1	c.-254C>G		5_prime_UTR_variant	Exon 1 of 11		XP_047283466.1
TRPC6	XM_017018221.3	c.-254C>G		5_prime_UTR_variant	Exon 1 of 11		XP_016873710.1
TRPC6	XM_047427509.1	c.-89+175C>G		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.-254C>G		5_prime_UTR_variant	Exon 1 of 13	1	NM_004621.6	ENSP00000340913.3
TRPC6	ENST00000526713.1	n.266-78959C>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.0975 AC: 14841 AN: 152140 Hom.: 1284 Cov.: 33

Gnomad AFR AF: 0.0379

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.162

Gnomad ASJ AF: 0.0922

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.103

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0804

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.119 AC: 28829 AN: 242268 Hom.: 2987 Cov.: 3 AF XY: 0.117 AC XY: 14465 AN XY: 123120

Gnomad4 AFR exome AF: 0.0381

Gnomad4 AMR exome AF: 0.183

Gnomad4 ASJ exome AF: 0.0938

Gnomad4 EAS exome AF: 0.423

Gnomad4 SAS exome AF: 0.235

Gnomad4 FIN exome AF: 0.0985

Gnomad4 NFE exome AF: 0.0796

Gnomad4 OTH exome AF: 0.111

GnomAD4 genome AF: 0.0976 AC: 14859 AN: 152258 Hom.: 1292 Cov.: 33 AF XY: 0.105 AC XY: 7794 AN XY: 74460

Gnomad4 AFR AF: 0.0378

Gnomad4 AMR AF: 0.162

Gnomad4 ASJ AF: 0.0922

Gnomad4 EAS AF: 0.463

Gnomad4 SAS AF: 0.268

Gnomad4 FIN AF: 0.103

Gnomad4 NFE AF: 0.0804

Gnomad4 OTH AF: 0.107

Alfa AF: 0.0906 Hom.: 90

Bravo AF: 0.0996

Asia WGS AF: 0.360 AC: 1251 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 31281825, 19380626, 23999069, 25603901) -

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Atypical hemolytic-uremic syndrome Benign:1

Aug 12, 2022

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Focal segmental glomerulosclerosis 2 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.1
DANN	Benign	0.73

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

Publications

LitVar

Other links and lift over

dbSNP: rs3824934; hg19: chr11-101454488;