5-136226039-A-T

Variant names:

• chr5-136226039-A-T
• rs1369843082
• NM_020389.3:c.2257T>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020389.3(TRPC7):​c.2257T>A​(p.Phe753Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,438,734 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: TRPC7 NM_020389.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.202
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12881655).

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.2257T>A	p.Phe753Ile	missense	Exon 9 of 12	NP_065122.1	Q9HCX4-1
	TRPC7	NM_001376901.1		c.2092T>A	p.Phe698Ile	missense	Exon 8 of 11	NP_001363830.1	Q70T25
	TRPC7	NM_001167577.2		c.2074T>A	p.Phe692Ile	missense	Exon 8 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.2257T>A	p.Phe753Ile	missense	Exon 9 of 12	ENSP00000426070.2	Q9HCX4-1
	TRPC7	ENST00000502753.4	TSL:5	c.2092T>A	p.Phe698Ile	missense	Exon 8 of 11	ENSP00000424854.3	Q70T25
	TRPC7	ENST00000378459.7	TSL:5	c.2074T>A	p.Phe692Ile	missense	Exon 8 of 11	ENSP00000367720.3	Q9HCX4-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1438734 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 713246

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33316

American (AMR) AF: 0.00 AC: 0 AN: 41330

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25664

East Asian (EAS) AF: 0.00 AC: 0 AN: 39306

South Asian (SAS) AF: 0.00 AC: 0 AN: 82540

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51898

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5728

European-Non Finnish (NFE) AF: 0.00000273 AC: 3 AN: 1099424

Other (OTH) AF: 0.00 AC: 0 AN: 59528

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000907115), which strongly suggests a high chance of mosaicism in these individuals.

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	Benign	0.068
BayesDel_addAF	Benign	-0.074	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.92
DEOGEN2	Benign	0.18	T
Eigen	Benign	-0.061
Eigen_PC	Benign	0.058
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.0095	T
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.46	N
PhyloP100		0.20
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	0.15	N
REVEL	Benign	0.15
Sift	Benign	0.38	T
Polyphen		0.0	B
Vest4		0.34
MutPred		0.32		Loss of methylation at K752 (P = 0.0445)
MVP		0.84
MPC		0.87
ClinPred		0.16	T
GERP RS		3.8
Varity_R		0.070
gMVP		0.28
Mutation Taster		=87/13	polymorphism

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: rs1369843082; hg19: chr5-135561727;