NM_004228.7:c.1093G>A

Variant names:

• chr19-48478573-G-A
• rs768292381
• NM_004228.7:c.1093G>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_004228.7(CYTH2):​c.1093G>A​(p.Glu365Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000837 in 1,612,888 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000098 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000082 (2 hom.)
• Consequence: CYTH2 NM_004228.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.65
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.3844723).
• BS2: High Homozygotes in GnomAdExome4 at 2 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004228.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYTH2	NM_004228.7	MANE Select	c.1093G>A	p.Glu365Lys	missense	Exon 11 of 12	NP_004219.3
	CYTH2	NM_017457.6		c.1096G>A	p.Glu366Lys	missense	Exon 12 of 13	NP_059431.1	Q99418-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CYTH2	ENST00000452733.7	TSL:1 MANE Select	c.1093G>A	p.Glu365Lys	missense	Exon 11 of 12	ENSP00000408236.2	Q99418-2
	CYTH2	ENST00000427476.4	TSL:1	c.1096G>A	p.Glu366Lys	missense	Exon 11 of 12	ENSP00000486578.1	A0A0D9SFG6
	CYTH2	ENST00000704950.1		c.1228G>A	p.Glu410Lys	missense	Exon 11 of 12	ENSP00000516062.1	A0A994J5E5

Frequencies

GnomAD3 genomes AF: 0.0000986 AC: 15 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000565

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000160 AC: 40 AN: 249318 AF XY: 0.000223

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000514

Gnomad NFE exome AF: 0.0000445

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.0000822 AC: 120 AN: 1460576 Hom.: 2 Cov.: 33 AF XY: 0.000114 AC XY: 83 AN XY: 726522

African (AFR) AF: 0.00 AC: 0 AN: 33466

American (AMR) AF: 0.00 AC: 0 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26042

East Asian (EAS) AF: 0.00 AC: 0 AN: 39676

South Asian (SAS) AF: 0.000720 AC: 62 AN: 86096

European-Finnish (FIN) AF: 0.000526 AC: 28 AN: 53248

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5756

European-Non Finnish (NFE) AF: 0.0000216 AC: 24 AN: 1111316

Other (OTH) AF: 0.0000829 AC: 5 AN: 60340

GnomAD4 genome AF: 0.0000985 AC: 15 AN: 152312 Hom.: 0 Cov.: 32 AF XY: 0.000107 AC XY: 8 AN XY: 74478

African (AFR) AF: 0.00 AC: 0 AN: 41580

American (AMR) AF: 0.00 AC: 0 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5168

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.000565 AC: 6 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000429 Hom.: 0

Bravo AF: 0.0000302

ExAC AF: 0.000132 AC: 16

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.073	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.060	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.38	T
MetaSVM	Benign	-0.39	T
MutationAssessor	Benign	1.7	L
PhyloP100		6.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.8	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.0090	D
Sift4G	Benign	0.070	T
Polyphen		0.48	P
Vest4		0.57
MutPred		0.50		Gain of methylation at E365 (P = 0.0127)
MVP		0.89
MPC		0.97
ClinPred		0.12	T
GERP RS		3.4
Varity_R		0.31
gMVP		0.89
Mutation Taster		=97/3	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

dbSNP: rs768292381; hg19: chr19-48981830;