4-121879767-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2 BP4_Strong BP6_Moderate BS1 BS2

The NM_001130698.2(TRPC3):c.2735A>C(p.Lys912Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00139 in 1,610,172 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00083 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0015 (47 hom.)
• Consequence: TRPC3 NM_001130698.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.26

Genes affected

TRPC3 (HGNC:12335): (transient receptor potential cation channel subfamily C member 3) The protein encoded by this gene is a membrane protein that can form a non-selective channel permeable to calcium and other cations. The encoded protein appears to be induced to form channels by a receptor tyrosine kinase-activated phosphatidylinositol second messenger system and also by depletion of intracellular calcium stores. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• PP2: Missense variant where missense usually causes diseases, TRPC3
• BP4: Computational evidence support a benign effect (MetaRNN=0.006897241).
• BP6: Variant 4-121879767-T-G is Benign according to our data. Variant chr4-121879767-T-G is described in ClinVar as [Benign]. Clinvar id is 2044150.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000827 (126/152314) while in subpopulation SAS AF= 0.0253 (122/4826). AF 95% confidence interval is 0.0216. There are 2 homozygotes in gnomad4. There are 90 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 127 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC3	NM_001130698.2	c.2735A>C	p.Lys912Thr	missense_variant	12/12	ENST00000379645.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC3	ENST00000379645.8	c.2735A>C	p.Lys912Thr	missense_variant	12/12	1	NM_001130698.2	P4
TRPC3	ENST00000264811.9	c.2516A>C	p.Lys839Thr	missense_variant	11/11	1		A2
TRPC3	ENST00000513531.1	c.2351A>C	p.Lys784Thr	missense_variant	10/10	1
TRPC3	ENST00000506449.1	c.*1743A>C		3_prime_UTR_variant, NMD_transcript_variant	12/12	1

Frequencies

GnomAD3 genomes AF: 0.000834 AC: 127 AN: 152196 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0255

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00296 AC: 731 AN: 246914 Hom.: 15 AF XY: 0.00423 AC XY: 565 AN XY: 133526

Gnomad AFR exome AF: 0.0000626

Gnomad AMR exome AF: 0.0000904

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0240

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000444

Gnomad OTH exome AF: 0.00217

GnomAD4 exome AF: 0.00145 AC: 2119 AN: 1457858 Hom.: 47 Cov.: 30 AF XY: 0.00215 AC XY: 1558 AN XY: 725154

Gnomad4 AFR exome AF: 0.0000903

Gnomad4 AMR exome AF: 0.0000683

Gnomad4 ASJ exome AF: 0.0000384

Gnomad4 EAS exome AF: 0.000102

Gnomad4 SAS exome AF: 0.0235

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000189

Gnomad4 OTH exome AF: 0.00133

GnomAD4 genome AF: 0.000827 AC: 126 AN: 152314 Hom.: 2 Cov.: 32 AF XY: 0.00121 AC XY: 90 AN XY: 74486

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0253

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000178

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00344 AC: 417

Asia WGS AF: 0.0100 AC: 38 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Aug 16, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.18
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.85	T;T;T
MetaRNN	Benign	0.0069	T;T;T
MetaSVM	Uncertain	-0.14	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.1	N;N;N
REVEL	Uncertain	0.35
Sift	Uncertain	0.019	D;D;D
Sift4G	Benign	0.099	T;T;T
Vest4		0.32
MVP		0.84
MPC		0.93
ClinPred		0.040	T
GERP RS		4.9
gMVP		0.80

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: rs145948370; hg19: chr4-122800922;