chr19-48473972-G-A

Variant names:

• chr19-48473972-G-A
• NM_004228.7:c.502G>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_004228.7(CYTH2):​c.502G>A​(p.Ala168Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,482 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CYTH2 NM_004228.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.99
• 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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.891

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CYTH2	NM_004228.7	c.502G>A	p.Ala168Thr	missense_variant	Exon 6 of 12	ENST00000452733.7	NP_004219.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CYTH2	ENST00000452733.7	c.502G>A	p.Ala168Thr	missense_variant	Exon 6 of 12	1	NM_004228.7	ENSP00000408236.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1461482 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727074

African (AFR) AF: 0.00 AC: 0 AN: 33458

American (AMR) AF: 0.00 AC: 0 AN: 44638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.00 AC: 0 AN: 39692

South Asian (SAS) AF: 0.00 AC: 0 AN: 86224

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111812

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 16, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.502G>A (p.A168T) alteration is located in exon 6 (coding exon 6) of the CYTH2 gene. This alteration results from a G to A substitution at nucleotide position 502, causing the alanine (A) at amino acid position 168 to be replaced by a threonine (T). 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	0.99
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	31
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.25	.;T;.;T;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Pathogenic	0.99	D;D;T;D;D;D
M_CAP	Benign	0.052	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Benign	-0.40	T
MutationAssessor	Uncertain	2.8	M;.;.;M;.;.
PhyloP100		10
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-3.8	D;.;.;.;D;.
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D;.;.;.;D;.
Sift4G	Uncertain	0.0090	D;D;.;.;D;D
Polyphen		1.0	D;.;.;.;.;.
Vest4		0.94
MutPred		0.76		Gain of phosphorylation at A168 (P = 0.0587);Gain of phosphorylation at A168 (P = 0.0587);.;Gain of phosphorylation at A168 (P = 0.0587);.;.;
MVP		0.78
MPC		1.8
ClinPred		0.99	D
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.39
gMVP		0.86
Mutation Taster		=47/53	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: chr19-48977229; COSMIC: COSV57308929; COSMIC: COSV57308929;