5-136225320-T-C

Variant names:

• chr5-136225320-T-C
• rs1755589720
• NM_020389.3:c.2297A>G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_020389.3(TRPC7):​c.2297A>G​(p.Glu766Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,180 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 (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TRPC7 NM_020389.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.61

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.35713726).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC7	NM_020389.3	c.2297A>G	p.Glu766Gly	missense_variant	Exon 10 of 12	ENST00000513104.6	NP_065122.1
TRPC7	NM_001376901.1	c.2132A>G	p.Glu711Gly	missense_variant	Exon 9 of 11		NP_001363830.1
TRPC7	NM_001167577.2	c.2114A>G	p.Glu705Gly	missense_variant	Exon 9 of 11		NP_001161049.1
TRPC7	NM_001167576.2	c.1949A>G	p.Glu650Gly	missense_variant	Exon 8 of 10		NP_001161048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC7	ENST00000513104.6	c.2297A>G	p.Glu766Gly	missense_variant	Exon 10 of 12	5	NM_020389.3	ENSP00000426070.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461180 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726728

Gnomad4 AFR exome AF: 0.0000299

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: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2297A>G (p.E766G) alteration is located in exon 10 (coding exon 10) of the TRPC7 gene. This alteration results from a A to G substitution at nucleotide position 2297, causing the glutamic acid (E) at amino acid position 766 to be replaced by a glycine (G). 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	0.098
BayesDel_addAF	Benign	-0.0038	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T;.;T;.
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.80	T;T;T;T
M_CAP	Benign	0.064	D
MetaRNN	Benign	0.36	T;T;T;T
MetaSVM	Uncertain	-0.26	T
MutationAssessor	Benign	1.3	L;.;.;.
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-3.0	D;D;D;D
REVEL	Uncertain	0.36
Sift	Benign	0.19	T;T;T;T
Polyphen		0.12	B;.;B;.
Vest4		0.42
MutPred		0.31		Gain of MoRF binding (P = 0.0377);.;.;.;
MVP		0.90
MPC		0.79
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.35
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.080		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: rs1755589720; hg19: chr5-135561008;