2-46581027-C-T

Variant names:

• chr2-46581027-C-T
• NM_012249.4:c.562C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_012249.4(RHOQ):​c.562C>T​(p.His188Tyr) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,436,290 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H188L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: RHOQ NM_012249.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.52
• Publications: 0 publications found

Genes affected

RHOQ (HGNC:17736): (ras homolog family member Q) This gene encodes a member of the Rho family of small GTPases, which cycle between inactive GDP-bound and active GTP-bound states and function as molecular switches in signal transduction cascades. Rho proteins promote reorganization of the actin cytoskeleton and regulate cell shape, attachment, and motility. The encoded protein is an important signalling protein for sarcomere assembly and has been shown to play a significant role in the exocytosis of the solute carrier family 2, facilitated glucose transporter member 4 and other proteins, possibly acting as the signal that turns on the membrane fusion machinery. Three related pseudogene have been identified on chromosomes 2 and 14. [provided by RefSeq, Aug 2011]

PIGF (HGNC:8962): (phosphatidylinositol glycan anchor biosynthesis class F) This gene encodes a protein involved in glycosylphosphatidylinositol (GPI)-anchor biosynthesis. The GPI-anchor, a glycolipid containing three mannose molecules in its core backbone, is found on many blood cells where it serves to anchor proteins to the cell surface. The encoded protein and another GPI synthesis protein, PIGO, function in the transfer of ethanolaminephosphate to the third mannose in GPI. Alternatively spliced transcript variants encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

PIGF Gene-Disease associations (from GenCC):

• onychodystrophy, osteodystrophy, impaired intellectual development, and seizures syndrome

  Inheritance: AR Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21126169).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RHOQ	NM_012249.4	c.562C>T	p.His188Tyr	missense_variant	Exon 5 of 5	ENST00000238738.9	NP_036381.2
PIGF	NM_002643.4	c.*451G>A		3_prime_UTR_variant	Exon 6 of 6	ENST00000281382.11	NP_002634.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RHOQ	ENST00000238738.9	c.562C>T	p.His188Tyr	missense_variant	Exon 5 of 5	1	NM_012249.4	ENSP00000238738.4
PIGF	ENST00000281382.11	c.*451G>A		3_prime_UTR_variant	Exon 6 of 6	1	NM_002643.4	ENSP00000281382.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1436290 Hom.: 0 Cov.: 27 AF XY: 0.00000140 AC XY: 1 AN XY: 714470

African (AFR) AF: 0.00 AC: 0 AN: 32066

American (AMR) AF: 0.00 AC: 0 AN: 39238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25184

East Asian (EAS) AF: 0.00 AC: 0 AN: 39050

South Asian (SAS) AF: 0.00 AC: 0 AN: 82066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53096

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4026

European-Non Finnish (NFE) AF: 9.07e-7 AC: 1 AN: 1102458

Other (OTH) AF: 0.00 AC: 0 AN: 59106

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 11, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562C>T (p.H188Y) alteration is located in exon 5 (coding exon 5) of the RHOQ gene. This alteration results from a C to T substitution at nucleotide position 562, causing the histidine (H) at amino acid position 188 to be replaced by a tyrosine (Y). 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	Benign	0.097
BayesDel_addAF	Benign	-0.044	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.18	T
Eigen	Benign	0.012
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.82	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.5
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.042
Sift	Benign	0.088	T
Sift4G	Uncertain	0.054	T
Polyphen		0.12	B
Vest4		0.28
MutPred		0.43		Loss of disorder (P = 0.0402);
MVP		0.76
MPC		0.90
ClinPred		0.68	D
GERP RS		4.6
Varity_R		0.13
gMVP		0.64
Mutation Taster		=78/22	polymorphism

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

Other links and lift over

hg19: chr2-46808166;