Genetic Variant TRPC7:p.Met727Thr (chr5-136226116-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020389.3(TRPC7):c.2180T>C(p.Met727Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000363 in 1,599,282 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000037 ( 0 hom. )

Consequence

TRPC7
NM_020389.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.36

Variant links:

Genes affected

TRPC7 (HGNC:20754): (transient receptor potential cation channel subfamily C member 7) Predicted to enable inositol 1,4,5 trisphosphate binding activity and store-operated calcium channel activity. Predicted to be involved in metal ion transport; regulation of cytosolic calcium ion concentration; and single fertilization. Predicted to act upstream of or within calcium ion transport. Predicted to be located in plasma membrane. Predicted to be part of cation channel complex. Predicted to be integral component of plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

TRPC7 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.17807981).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC7	NM_020389.3 link	c.2180T>C	p.Met727Thr	missense_variant	Exon 9 of 12	ENST00000513104.6	NP_065122.1	Q9HCX4-1
TRPC7	NM_001376901.1 link	c.2015T>C	p.Met672Thr	missense_variant	Exon 8 of 11		NP_001363830.1
TRPC7	NM_001167577.2 link	c.1997T>C	p.Met666Thr	missense_variant	Exon 8 of 11		NP_001161049.1	Q9HCX4-3
TRPC7	NM_001167576.2 link	c.1832T>C	p.Met611Thr	missense_variant	Exon 7 of 10		NP_001161048.1	Q9HCX4-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC7	ENST00000513104.6 link	c.2180T>C	p.Met727Thr	missense_variant	Exon 9 of 12	5	NM_020389.3	ENSP00000426070.2		Q9HCX4-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

225448

Hom.:

AF XY:

0.0000247

AC XY:

AN XY:

121386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000899

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000366

AC:

AN:

1447086

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

718110

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000190

Gnomad4 NFE exome

AF:

0.0000444

Gnomad4 OTH exome

AF:

0.0000501

GnomAD4 genome

AF:

0.0000329

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74346

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000941

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000658

Hom.:

Bravo

AF:

0.0000340

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000122

AC:

ExAC

AF:

0.0000663

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2180T>C (p.M727T) alteration is located in exon 9 (coding exon 9) of the TRPC7 gene. This alteration results from a T to C substitution at nucleotide position 2180, causing the methionine (M) at amino acid position 727 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.092

BayesDel_addAF

Benign

-0.11

BayesDel_noAF

Benign

-0.20

CADD

Benign

DANN

Benign

0.84

DEOGEN2

Benign

0.20

T;.;T;.

Eigen

Benign

-0.29

Eigen_PC

Benign

-0.058

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.76

T;T;T;T

M_CAP

Benign

0.017

MetaRNN

Benign

0.18

T;T;T;T

MetaSVM

Benign

-0.85

MutationAssessor

Benign

0.41

N;.;.;.

PrimateAI

Uncertain

0.77

PROVEAN

Benign

-0.28

N;N;N;N

REVEL

Benign

0.23

Sift

Benign

0.42

T;T;T;T

Polyphen

0.0

B;.;B;.

Vest4

0.37

MVP

0.75

MPC

0.72

ClinPred

0.11

GERP RS

5.0

Varity_R

0.12

gMVP

0.22

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over