X-111776495-G-C

Variant names:

• chrX-111776495-G-C
• rs764629984
• NM_012471.3:c.2740C>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_012471.3(TRPC5):​c.2740C>G​(p.Gln914Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000638 in 1,097,262 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000064 (0 hom. 4 hem.)
• Consequence: TRPC5 NM_012471.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.84

Genes affected

TRPC5 (HGNC:12337): (transient receptor potential cation channel subfamily C member 5) This gene belongs to the transient receptor family. It encodes one of the seven mammalian TRPC (transient receptor potential channel) proteins. The encoded protein is a multi-pass membrane protein and is thought to form a receptor-activated non-selective calcium permeant cation channel. The protein is active alone or as a heteromultimeric assembly with TRPC1, TRPC3, and TRPC4. It also interacts with multiple proteins including calmodulin, CABP1, enkurin, Na(+)-H+ exchange regulatory factor (NHERF ), interferon-induced GTP-binding protein (MX1), ring finger protein 24 (RNF24), and SEC14 domain and spectrin repeat-containing protein 1 (SESTD1). [provided by RefSeq, May 2010]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06676075).
• BS2: High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TRPC5	NM_012471.3	c.2740C>G	p.Gln914Glu	missense_variant	Exon 11 of 11	ENST00000262839.3	NP_036603.1
TRPC5	XM_017029774.2	c.2740C>G	p.Gln914Glu	missense_variant	Exon 12 of 12		XP_016885263.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TRPC5	ENST00000262839.3	c.2740C>G	p.Gln914Glu	missense_variant	Exon 11 of 11	1	NM_012471.3	ENSP00000262839.2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD3 exomes AF: 0.00000552 AC: 1 AN: 181026 Hom.: 0 AF XY: 0.0000152 AC XY: 1 AN XY: 65888

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 SAS exome AF: 0.0000534

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000638 AC: 7 AN: 1097262 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 4 AN XY: 362702

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: 0.0000741

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000356

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 23

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

TRPC5-related disorder Uncertain:1

Aug 01, 2023

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The TRPC5 c.2740C>G variant is predicted to result in the amino acid substitution p.Gln914Glu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0053% of alleles in individuals of South Asian descent in gnomAD, including one hemizygous indivdiual (http://gnomad.broadinstitute.org/variant/X-111019723-G-C). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	11
DANN	Benign	0.95
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.55	T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.067	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.55	N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.57	N
REVEL	Benign	0.11
Sift	Benign	0.28	T
Sift4G	Benign	1.0	T
Polyphen		0.0010	B
Vest4		0.020
MutPred		0.12		Gain of glycosylation at S916 (P = 0.0687);
MVP		0.47
MPC		0.18
ClinPred		0.091	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.073

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: rs764629984; hg19: chrX-111019723;