5-136231375-G-C

Variant names:

• chr5-136231375-G-C
• rs1755808118
• NM_020389.3:c.2019C>G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_020389.3(TRPC7):​c.2019C>G​(p.Asn673Lys) variant causes a missense change. The variant allele was found at a frequency of 0.000000692 in 1,445,446 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: 6.9e-7 (0 hom.)
• Consequence: TRPC7 NM_020389.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.84

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-AS2 (HGNC:40937): (TRPC7 antisense RNA 2)

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC7	NM_020389.3	c.2019C>G	p.Asn673Lys	missense_variant	Exon 8 of 12	ENST00000513104.6	NP_065122.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC7	ENST00000513104.6	c.2019C>G	p.Asn673Lys	missense_variant	Exon 8 of 12	5	NM_020389.3	ENSP00000426070.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.92e-7 AC: 1 AN: 1445446 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 715166

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: 9.10e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 25, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2019C>G (p.N673K) alteration is located in exon 8 (coding exon 8) of the TRPC7 gene. This alteration results from a C to G substitution at nucleotide position 2019, causing the asparagine (N) at amino acid position 673 to be replaced by a lysine (K). 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	Uncertain	0.087	D
BayesDel_noAF	Benign	-0.11
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;.;D;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D;D;D;D
M_CAP	Benign	0.084	D
MetaRNN	Pathogenic	0.91	D;D;D;D
MetaSVM	Uncertain	-0.082	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-4.5	D;D;D;D
REVEL	Pathogenic	0.68
Sift	Uncertain	0.0020	D;D;D;D
Polyphen		0.99	D;.;D;.
Vest4		0.95
MutPred		0.77		Gain of ubiquitination at N673 (P = 0.0203);.;.;.;
MVP		0.88
MPC		1.7
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.78
gMVP		0.96

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: rs1755808118; hg19: chr5-135567063;