19-48470484-G-A

Variant names:

• chr19-48470484-G-A
• NM_004228.7:c.151G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_004228.7(CYTH2):​c.151G>A​(p.Glu51Lys) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CYTH2 NM_004228.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.50
• Publications: 0 publications found

Genes affected

CYTH2 (HGNC:9502): (cytohesin 2) The protein encoded by this gene is a member of the PSCD family. Members of this family have identical structural organization that consists of an N-terminal coiled-coil motif, a central Sec7 domain, and a C-terminal pleckstrin homology (PH) domain. The coiled-coil motif is involved in homodimerization, the Sec7 domain contains guanine-nucleotide exchange protein (GEP) activity, and the PH domain interacts with phospholipids and is responsible for association of PSCDs with membranes. Members of this family appear to mediate the regulation of protein sorting and membrane trafficking. The encoded protein exhibits GEP activity in vitro with ARF1, ARF3, and ARF6 and is 83% homologous to CYTH1. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2008]

ENSG00000268465 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3252924).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH2	NM_004228.7	c.151G>A	p.Glu51Lys	missense_variant	Exon 2 of 12	ENST00000452733.7	NP_004219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYTH2	ENST00000452733.7	c.151G>A	p.Glu51Lys	missense_variant	Exon 2 of 12	1	NM_004228.7	ENSP00000408236.2
ENSG00000268465	ENST00000595676.1	c.103G>A	p.Glu35Lys	missense_variant	Exon 2 of 4	2		ENSP00000470383.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.151G>A (p.E51K) alteration is located in exon 2 (coding exon 2) of the CYTH2 gene. This alteration results from a G to A substitution at nucleotide position 151, causing the glutamic acid (E) at amino acid position 51 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	0.63
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.034	.;.;T;.;T;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.33	T;T;T;T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	.;M;.;.;M;.
PhyloP100		3.5
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	.;N;.;.;.;N
REVEL	Benign	0.16
Sift	Benign	0.13	.;T;.;.;.;T
Sift4G	Benign	0.22	T;T;T;.;.;T
Polyphen		0.43	.;B;.;.;.;.
Vest4		0.42, 0.44
MutPred		0.30		.;Gain of ubiquitination at E51 (P = 9e-04);Gain of ubiquitination at E51 (P = 9e-04);Gain of ubiquitination at E51 (P = 9e-04);Gain of ubiquitination at E51 (P = 9e-04);.;
MVP		0.32
MPC		0.91
ClinPred		0.97	D
GERP RS		5.4
Varity_R		0.93
gMVP		0.54
Mutation Taster		=49/51	disease causing

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: chr19-48973741;