Genetic Variant NM_004621.6:c.29G>A (chr11-101583475-C-T) – ACMG Classification: Likely_benign (-1 pts)

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS2_Supporting

The NM_004621.6(TRPC6):c.29G>A(p.Arg10Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000367 in 1,363,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R10R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000037 ( 0 hom. )

Consequence

TRPC6
NM_004621.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.80

Publications

0 publications found

Variant links:

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

TRPC6 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.25315732).

BS2

High AC in GnomAdExome4 at 5 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC6	NM_004621.6 link	c.29G>A	p.Arg10Gln	missense_variant	Exon 1 of 13	ENST00000344327.8	NP_004612.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC6	ENST00000344327.8 link	c.29G>A	p.Arg10Gln	missense_variant	Exon 1 of 13	1	NM_004621.6	ENSP00000340913.3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

123968

AF XY:

0.0000294

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000913

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000367

AC:

AN:

1363642

Hom.:

Cov.:

AF XY:

0.00000448

AC XY:

AN XY:

669130

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29252

American (AMR)

AF:

0.0000597

AC:

AN:

33514

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24150

East Asian (EAS)

AF:

0.00

AC:

AN:

34394

South Asian (SAS)

AF:

0.00

AC:

AN:

77080

European-Finnish (FIN)

AF:

0.00

AC:

AN:

41706

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5076

European-Non Finnish (NFE)

AF:

0.00000282

AC:

AN:

1062022

Other (OTH)

AF:

0.00

AC:

AN:

56448

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.445

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 10, 2017

Athena Diagnostics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.22

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.21

T;.;.;.

Eigen

Benign

-0.19

Eigen_PC

Benign

-0.095

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Uncertain

0.23

MetaRNN

Benign

0.25

T;T;T;T

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.55

N;.;N;N

PhyloP100

3.8

PrimateAI

Pathogenic

0.81

PROVEAN

Benign

-0.41

N;N;N;N

REVEL

Uncertain

0.31

Sift

Uncertain

0.016

D;D;D;D

Sift4G

Benign

0.25

T;T;T;T

Polyphen

0.21

B;.;B;B

Vest4

0.25

MutPred

0.30

Loss of MoRF binding (P = 0.0105);Loss of MoRF binding (P = 0.0105);Loss of MoRF binding (P = 0.0105);Loss of MoRF binding (P = 0.0105);

MVP

0.78

MPC

0.34

ClinPred

0.34

GERP RS

5.2

PromoterAI

-0.024

Neutral

(source)

Varity_R

0.17

gMVP

0.41

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over