rs4542378

Variant names:

• chr11-101503895-G-A
• rs4542378
• NM_004621.6:c.945+129C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-101503895-G-A
• chr11-101503895-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.945+129C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 1,145,114 control chromosomes in the GnomAD database, including 110,200 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16385 hom., cov: 32)
  • Exomes 𝑓: 0.43 (93815 hom.)
• Consequence: TRPC6 NM_004621.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0700
• Publications: 4 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=-0.88).
• BP6: Variant 11-101503895-G-A is Benign according to our data. Variant chr11-101503895-G-A is described in ClinVar as Benign. ClinVar VariationId is 1231268.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.541 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6	c.945+129C>T		intron_variant	Intron 2 of 12	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8	c.945+129C>T		intron_variant	Intron 2 of 12	1	NM_004621.6	ENSP00000340913.3

Frequencies

GnomAD3 genomes AF: 0.459 AC: 69709 AN: 151944 Hom.: 16368 Cov.: 32

Gnomad AFR AF: 0.546

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.395

Gnomad ASJ AF: 0.464

Gnomad EAS AF: 0.186

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.439

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.450

Gnomad OTH AF: 0.444

GnomAD4 exome AF: 0.429 AC: 426502 AN: 993052 Hom.: 93815 AF XY: 0.428 AC XY: 217504 AN XY: 507658

African (AFR) AF: 0.557 AC: 13207 AN: 23722

American (AMR) AF: 0.363 AC: 14773 AN: 40736

Ashkenazi Jewish (ASJ) AF: 0.443 AC: 9892 AN: 22314

East Asian (EAS) AF: 0.213 AC: 7812 AN: 36610

South Asian (SAS) AF: 0.378 AC: 27849 AN: 73660

European-Finnish (FIN) AF: 0.430 AC: 21309 AN: 49584

Middle Eastern (MID) AF: 0.463 AC: 2024 AN: 4368

European-Non Finnish (NFE) AF: 0.445 AC: 310569 AN: 697776

Other (OTH) AF: 0.431 AC: 19067 AN: 44282

GnomAD4 genome AF: 0.459 AC: 69787 AN: 152062 Hom.: 16385 Cov.: 32 AF XY: 0.455 AC XY: 33820 AN XY: 74326

African (AFR) AF: 0.546 AC: 22666 AN: 41478

American (AMR) AF: 0.396 AC: 6045 AN: 15280

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

East Asian (EAS) AF: 0.186 AC: 960 AN: 5164

South Asian (SAS) AF: 0.371 AC: 1786 AN: 4816

European-Finnish (FIN) AF: 0.439 AC: 4640 AN: 10558

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

European-Non Finnish (NFE) AF: 0.450 AC: 30565 AN: 67984

Other (OTH) AF: 0.446 AC: 943 AN: 2114

Alfa AF: 0.438 Hom.: 4899

Bravo AF: 0.460

Asia WGS AF: 0.309 AC: 1076 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

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

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Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	1.4
DANN	Benign	0.67
PhyloP100		0.070
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: rs4542378; hg19: chr11-101374626; COSMIC: COSV60252133; COSMIC: COSV60252133;