2-55291746-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001365480.1(CCDC88A):c.5581T>G(p.Ser1861Ala) variant causes a missense change. 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S1861L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC88A NM_001365480.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.03

Genes affected

CCDC88A (HGNC:25523): (coiled-coil domain containing 88A) This gene encodes a member of the Girdin family of coiled-coil domain containing proteins. The encoded protein is an actin-binding protein that is activated by the serine/threonine kinase Akt and plays a role in cytoskeleton remodeling and cell migration. The encoded protein also enhances Akt signaling by mediating phosphoinositide 3-kinase (PI3K)-dependent activation of Akt by growth factor receptor tyrosine kinases and G protein-coupled receptors. Increased expression of this gene and phosphorylation of the encoded protein may play a role in cancer metastasis. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2011]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.22615919).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88A	NM_001365480.1	c.5581T>G	p.Ser1861Ala	missense_variant	32/33	ENST00000436346.7
CCDC88A	NM_001135597.2	c.5578T>G	p.Ser1860Ala	missense_variant	32/33
CCDC88A	NM_018084.5	c.5497T>G	p.Ser1833Ala	missense_variant	31/32
CCDC88A	NM_001254943.2	c.5356T>G	p.Ser1786Ala	missense_variant	33/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88A	ENST00000436346.7	c.5581T>G	p.Ser1861Ala	missense_variant	32/33	5	NM_001365480.1	A1
	ENST00000625718.2	n.85+9312A>C		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 14, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CCDC88A-related conditions. This variant is not present in population databases (ExAC no frequency). This sequence change replaces serine with alanine at codon 1860 of the CCDC88A protein (p.Ser1860Ala). The serine residue is moderately conserved and there is a moderate physicochemical difference between serine and alanine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.042	T
BayesDel_noAF	Benign	-0.30
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.31
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.69	T;T;T;.;T;T;T;T;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationTaster	Benign	0.92	D;D;D;D;N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.1	N;N;.;.;.;N;.;.;.;N;.;.
REVEL	Benign	0.087
Sift	Pathogenic	0.0	D;D;.;.;.;D;.;.;.;D;.;.
Sift4G	Benign	0.16	T;T;.;.;.;T;.;.;.;D;.;.
Polyphen		0.99	D;D;D;.;.;.;.;.;.;.;.;.
Vest4		0.34
MVP		0.52
MPC		0.049
ClinPred		0.93	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.29
gMVP		0.42

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: chr2-55518882;