5-136213562-T-C

Variant names:

• chr5-136213562-T-C
• rs1484601445
• NM_020389.3:c.2462A>G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020389.3(TRPC7):​c.2462A>G​(p.Tyr821Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,700 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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: 7.77

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.829

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC7	NM_020389.3	c.2462A>G	p.Tyr821Cys	missense_variant	Exon 12 of 12	ENST00000513104.6	NP_065122.1
TRPC7	NM_001376901.1	c.2297A>G	p.Tyr766Cys	missense_variant	Exon 11 of 11		NP_001363830.1
TRPC7	NM_001167577.2	c.2279A>G	p.Tyr760Cys	missense_variant	Exon 11 of 11		NP_001161049.1
TRPC7	NM_001167576.2	c.2114A>G	p.Tyr705Cys	missense_variant	Exon 10 of 10		NP_001161048.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC7	ENST00000513104.6	c.2462A>G	p.Tyr821Cys	missense_variant	Exon 12 of 12	5	NM_020389.3	ENSP00000426070.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461700 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727132

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: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 09, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2462A>G (p.Y821C) alteration is located in exon 12 (coding exon 12) of the TRPC7 gene. This alteration results from a A to G substitution at nucleotide position 2462, causing the tyrosine (Y) at amino acid position 821 to be replaced by a cysteine (C). 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	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.60	D;.;T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.83	D;D;D;D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L;.;.;.
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.2	D;D;D;D
REVEL	Pathogenic	0.76
Sift	Benign	0.033	D;D;T;T
Polyphen		0.38	B;.;B;.
Vest4		0.86
MutPred		0.56		Loss of catalytic residue at Y821 (P = 0.1891);.;.;.;
MVP		0.84
MPC		0.89
ClinPred		0.99	D
GERP RS		4.9
Varity_R		0.49
gMVP		0.62

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

Other links and lift over

dbSNP: rs1484601445; hg19: chr5-135549250;