9-122855334-C-T

Variant names:

• chr9-122855334-C-T
• NM_001100588.3:c.2665G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001100588.3(RC3H2):​c.2665G>A​(p.Glu889Lys) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RC3H2 NM_001100588.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.12

Genes affected

RC3H2 (HGNC:21461): (ring finger and CCCH-type domains 2) Enables nucleic acid binding activity and ubiquitin protein ligase activity. Involved in protein polyubiquitination. Located in cell surface; intracellular membrane-bounded organelle; and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RC3H2	NM_001100588.3	c.2665G>A	p.Glu889Lys	missense_variant	Exon 15 of 21	ENST00000357244.7	NP_001094058.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RC3H2	ENST00000357244.7	c.2665G>A	p.Glu889Lys	missense_variant	Exon 15 of 21	5	NM_001100588.3	ENSP00000349783.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 06, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2665G>A (p.E889K) alteration is located in exon 15 (coding exon 14) of the RC3H2 gene. This alteration results from a G to A substitution at nucleotide position 2665, causing the glutamic acid (E) at amino acid position 889 to be replaced by a lysine (K). 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	0.77
BayesDel_addAF	Benign	-0.0061	T
BayesDel_noAF	Benign	-0.25
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.;T
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.74	T
MutationAssessor	Benign	1.8	L;L;L;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-2.1	N;N;N;D
REVEL	Benign	0.19
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.011	D;D;D;D
Polyphen		0.95	P;P;D;.
Vest4		0.31
MutPred		0.41		Gain of methylation at E889 (P = 0.0053);Gain of methylation at E889 (P = 0.0053);Gain of methylation at E889 (P = 0.0053);.;
MVP		0.21
MPC		0.75
ClinPred		0.91	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.67

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: chr9-125617613;