chr5-136213562-T-C

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 0 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-AS1 (HGNC:40936): (TRPC7 antisense RNA 1)

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, 0.829

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.2462A>G	p.Tyr821Cys	missense	Exon 12 of 12	NP_065122.1	Q9HCX4-1
	TRPC7	NM_001376901.1		c.2297A>G	p.Tyr766Cys	missense	Exon 11 of 11	NP_001363830.1	Q70T25
	TRPC7	NM_001167577.2		c.2279A>G	p.Tyr760Cys	missense	Exon 11 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.2462A>G	p.Tyr821Cys	missense	Exon 12 of 12	ENSP00000426070.2	Q9HCX4-1
	TRPC7	ENST00000502753.4	TSL:5	c.2297A>G	p.Tyr766Cys	missense	Exon 11 of 11	ENSP00000424854.3	Q70T25
	TRPC7	ENST00000378459.7	TSL:5	c.2279A>G	p.Tyr760Cys	missense	Exon 11 of 11	ENSP00000367720.3	Q9HCX4-3

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

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111870

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

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	0.98
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Uncertain	26
DANN	Benign	0.96
DEOGEN2	Uncertain	0.60	D
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.056	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.16	D
MutationAssessor	Benign	1.6	L
PhyloP100		7.8
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.2	D
REVEL	Pathogenic	0.76
Sift	Benign	0.033	D
Polyphen		0.38	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
Mutation Taster		=27/73	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: rs1484601445; hg19: chr5-135549250;