Genetic Variant TRPC7:p.Ala760Asp (chr5-136225338-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_020389.3(TRPC7):c.2279C>A(p.Ala760Asp) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,460,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A760V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TRPC7
NM_020389.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.96

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.23922497).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC7	NM_020389.3 link	c.2279C>A	p.Ala760Asp	missense_variant	Exon 10 of 12	ENST00000513104.6	NP_065122.1	Q9HCX4-1
TRPC7	NM_001376901.1 link	c.2114C>A	p.Ala705Asp	missense_variant	Exon 9 of 11		NP_001363830.1
TRPC7	NM_001167577.2 link	c.2096C>A	p.Ala699Asp	missense_variant	Exon 9 of 11		NP_001161049.1	Q9HCX4-3
TRPC7	NM_001167576.2 link	c.1931C>A	p.Ala644Asp	missense_variant	Exon 8 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.2279C>A	p.Ala760Asp	missense_variant	Exon 10 of 12	5	NM_020389.3	ENSP00000426070.2		Q9HCX4-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1460846

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726520

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33472

American (AMR)

AF:

0.00

AC:

AN:

44654

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26100

East Asian (EAS)

AF:

0.00

AC:

AN:

39692

South Asian (SAS)

AF:

0.00

AC:

AN:

85858

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53376

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111568

Other (OTH)

AF:

0.0000166

AC:

AN:

60360

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.400

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Benign

-0.19

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.28

T;.;T;.

Eigen

Benign

0.14

Eigen_PC

Uncertain

0.29

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

D;D;D;D

M_CAP

Benign

0.020

MetaRNN

Benign

0.24

T;T;T;T

MetaSVM

Benign

-0.34

MutationAssessor

Benign

1.8

L;.;.;.

PhyloP100

7.0

PrimateAI

Benign

0.45

PROVEAN

Benign

-1.0

N;N;N;N

REVEL

Benign

0.19

Sift

Benign

0.050

D;T;D;T

Polyphen

0.0090

B;.;B;.

Vest4

0.38

MutPred

0.34

Loss of catalytic residue at A760 (P = 0.0222);.;.;.;

MVP

0.90

MPC

0.95

ClinPred

0.78

GERP RS

5.0

Varity_R

0.37

gMVP

0.52

Mutation Taster

=71/29

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.16

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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5-136225338-G-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over