2-55295671-G-T

Variant summary

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

The NM_001365480.1(CCDC88A):c.5477C>A(p.Thr1826Asn) variant causes a missense change. The variant allele was found at a frequency of 0.00000124 in 1,614,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• 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=0.121296495).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC88A	NM_001365480.1	c.5477C>A	p.Thr1826Asn	missense_variant	31/33	ENST00000436346.7
CCDC88A	NM_001135597.2	c.5474C>A	p.Thr1825Asn	missense_variant	31/33
CCDC88A	NM_018084.5	c.5393C>A	p.Thr1798Asn	missense_variant	30/32
CCDC88A	NM_001254943.2	c.5252C>A	p.Thr1751Asn	missense_variant	32/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88A	ENST00000436346.7	c.5477C>A	p.Thr1826Asn	missense_variant	31/33	5	NM_001365480.1	A1
	ENST00000625718.2	n.86-13161G>T		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461892 Hom.: 0 Cov.: 34 AF XY: 0.00000138 AC XY: 1 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000478

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

Oct 20, 2021

This sequence change replaces threonine with asparagine at codon 1825 of the CCDC88A protein (p.Thr1825Asn). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with CCDC88A-related conditions. 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"). 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	21
Dann	Benign	0.95
Eigen	Benign	-0.29
Eigen_PC	Benign	-0.12
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;.;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0042	T
MetaRNN	Benign	0.12	T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.48	N;N;.;.;.;N;.;.;.;N;.;.;N
REVEL	Benign	0.073
Sift	Benign	0.073	T;T;.;.;.;T;.;.;.;D;.;.;T
Sift4G	Benign	0.21	T;T;.;.;.;T;.;.;.;D;.;.;T
Polyphen		0.012	B;B;B;B;.;B;.;.;.;.;.;.;.
Vest4		0.18
MutPred		0.074		.;.;.;Loss of phosphorylation at T1826 (P = 0.0421);.;Loss of phosphorylation at T1826 (P = 0.0421);.;.;.;.;.;.;.;
MVP		0.33
MPC		0.038
ClinPred		0.31	T
GERP RS		2.4
Varity_R		0.048
gMVP		0.25

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

LitVar

Other links and lift over

dbSNP: rs1679949384; hg19: chr2-55522807;