NM_020389.3:c.1936G>A

Variant names:

• chr5-136231458-C-T
• rs761895627
• NM_020389.3:c.1936G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_020389.3(TRPC7):​c.1936G>A​(p.Glu646Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000411 in 1,460,636 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: 0.0000041 (0 hom.)
• Consequence: TRPC7 NM_020389.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91
• Publications: 2 publications found

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

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.836

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_020389.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC7	NM_020389.3	MANE Select	c.1936G>A	p.Glu646Lys	missense	Exon 8 of 12	NP_065122.1	Q9HCX4-1
	TRPC7	NM_001376901.1		c.1771G>A	p.Glu591Lys	missense	Exon 7 of 11	NP_001363830.1	Q70T25
	TRPC7	NM_001167577.2		c.1753G>A	p.Glu585Lys	missense	Exon 7 of 11	NP_001161049.1	Q9HCX4-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TRPC7	ENST00000513104.6	TSL:5 MANE Select	c.1936G>A	p.Glu646Lys	missense	Exon 8 of 12	ENSP00000426070.2	Q9HCX4-1
	TRPC7	ENST00000502753.4	TSL:5	c.1771G>A	p.Glu591Lys	missense	Exon 7 of 11	ENSP00000424854.3	Q70T25
	TRPC7	ENST00000378459.7	TSL:5	c.1753G>A	p.Glu585Lys	missense	Exon 7 of 11	ENSP00000367720.3	Q9HCX4-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000405 AC: 1 AN: 247058 AF XY: 0.00000747

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460636 Hom.: 0 Cov.: 31 AF XY: 0.00000551 AC XY: 4 AN XY: 726420

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44616

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26074

East Asian (EAS) AF: 0.00 AC: 0 AN: 39670

South Asian (SAS) AF: 0.0000233 AC: 2 AN: 85934

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111364

Other (OTH) AF: 0.00 AC: 0 AN: 60354

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000827 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.97
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.85	D
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.38	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		7.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-2.6	D
REVEL	Pathogenic	0.86
Sift	Benign	0.038	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.68		Gain of methylation at E646 (P = 0.0053)
MVP		0.93
MPC		1.6
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.55
gMVP		0.96
Mutation Taster		=44/56	disease causing

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

Other links and lift over

dbSNP: rs761895627; hg19: chr5-135567146; COSMIC: COSV61464057;