4-121879816-T-C

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.2686A>G(p.Ser896Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00174 in 1,608,510 control chromosomes in the GnomAD database, including 93 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0023 (11 hom., cov: 32)
  • Exomes 𝑓: 0.0017 (82 hom.)
• Consequence: TRPC3 NM_001130698.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.98

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=0.0073967576).
• BP6: Variant 4-121879816-T-C is Benign according to our data. Variant chr4-121879816-T-C is described in ClinVar as [Benign]. Clinvar id is 779331.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00226 (344/152320) while in subpopulation AMR AF= 0.0199 (304/15302). AF 95% confidence interval is 0.018. There are 11 homozygotes in gnomad4. There are 197 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 346 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TRPC3	NM_001130698.2	c.2686A>G	p.Ser896Gly	missense_variant	12/12	ENST00000379645.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TRPC3	ENST00000379645.8	c.2686A>G	p.Ser896Gly	missense_variant	12/12	1	NM_001130698.2	P4
TRPC3	ENST00000264811.9	c.2467A>G	p.Ser823Gly	missense_variant	11/11	1		A2
TRPC3	ENST00000513531.1	c.2302A>G	p.Ser768Gly	missense_variant	10/10	1
TRPC3	ENST00000506449.1	c.*1694A>G		3_prime_UTR_variant, NMD_transcript_variant	12/12	1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 346 AN: 152202 Hom.: 12 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0200

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000162

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00780 AC: 1909 AN: 244622 Hom.: 73 AF XY: 0.00615 AC XY: 814 AN XY: 132310

Gnomad AFR exome AF: 0.000502

Gnomad AMR exome AF: 0.0566

Gnomad ASJ exome AF: 0.000799

Gnomad EAS exome AF: 0.000280

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000986

Gnomad OTH exome AF: 0.00456

GnomAD4 exome AF: 0.00168 AC: 2451 AN: 1456190 Hom.: 82 Cov.: 30 AF XY: 0.00145 AC XY: 1049 AN XY: 724158

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.0517

Gnomad4 ASJ exome AF: 0.000997

Gnomad4 EAS exome AF: 0.000204

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.0000784

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152320 Hom.: 11 Cov.: 32 AF XY: 0.00264 AC XY: 197 AN XY: 74492

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.0199

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000162

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000599 Hom.: 1

Bravo AF: 0.00549

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00600 AC: 729

Asia WGS AF: 0.000577 AC: 2 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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Uncertain	-0.030
Cadd	Uncertain	24
Dann	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D;D
MetaRNN	Benign	0.0074	T;T;T
MetaSVM	Benign	-0.59	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.0	N;N;N
REVEL	Uncertain	0.49
Sift	Uncertain	0.0050	D;D;D
Sift4G	Benign	0.12	T;T;T
Vest4		0.39
MVP		0.75
MPC		0.84
ClinPred		0.039	T
GERP RS		4.9
gMVP		0.50

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: rs142202711; hg19: chr4-122800971;