7-122698142-G-C

Position:

• chr7-122698142-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_139175.2(RNF133):​c.777C>G​(p.Cys259Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RNF133 NM_139175.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70

Genes affected

RNF133 (HGNC:21154): (ring finger protein 133) The protein encoded by this gene contains a RING finger domain, a motif present in a variety of functionally distinct proteins and known to be involved in protein-protein and protein-DNA interactions. This gene has no intron. [provided by RefSeq, Jul 2008]

CADPS2 (HGNC:16018): (calcium dependent secretion activator 2) This gene encodes a member of the calcium-dependent activator of secretion (CAPS) protein family, which are calcium binding proteins that regulate the exocytosis of synaptic and dense-core vesicles in neurons and neuroendocrine cells. Mutations in this gene may contribute to autism susceptibility. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Nov 2009]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.992

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RNF133	NM_139175.2	c.777C>G	p.Cys259Trp	missense_variant	1/1	ENST00000340112.3	NP_631914.1
CADPS2	NM_017954.11	c.454-34573C>G		intron_variant		ENST00000449022.7	NP_060424.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RNF133	ENST00000340112.3	c.777C>G	p.Cys259Trp	missense_variant	1/1	6	NM_139175.2	ENSP00000344489.2
CADPS2	ENST00000449022.7	c.454-34573C>G		intron_variant		5	NM_017954.11	ENSP00000398481.2
CADPS2	ENST00000412584.6	c.454-34573C>G		intron_variant		1		ENSP00000400401.2
CADPS2	ENST00000313070.11	c.136-34573C>G		intron_variant		5		ENSP00000325581.8

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 22, 2024

The c.777C>G (p.C259W) alteration is located in exon 1 (coding exon 1) of the RNF133 gene. This alteration results from a C to G substitution at nucleotide position 777, causing the cysteine (C) at amino acid position 259 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.43
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.27	T
Eigen	Uncertain	0.68
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.97	D
M_CAP	Pathogenic	0.56	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Pathogenic	4.8	H
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-10	D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.90
MutPred		0.88		Loss of sheet (P = 0.0817);
MVP		1.0
MPC		0.17
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.89
gMVP		0.63

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr7-122338196;