2-55291715-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4BS1_Supporting

The NM_001365480.1(CCDC88A):c.5612C>T(p.Ser1871Phe) variant causes a missense change. The variant allele was found at a frequency of 0.000113 in 1,606,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

CCDC88A
NM_001365480.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.31

Variant links:

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]

CCDC88A links:

(HGNC:):

links:

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ACMG classification

Classification made for transcript

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=0.34195703).

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000526 (8/152174) while in subpopulation NFE AF= 0.000118 (8/68014). AF 95% confidence interval is 0.0000584. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
CCDC88A	NM_001365480.1 linkuse as main transcript	c.5612C>T	p.Ser1871Phe	missense_variant	32/33	ENST00000436346.7
CCDC88A	NM_001135597.2 linkuse as main transcript	c.5609C>T	p.Ser1870Phe	missense_variant	32/33
CCDC88A	NM_018084.5 linkuse as main transcript	c.5528C>T	p.Ser1843Phe	missense_variant	31/32
CCDC88A	NM_001254943.2 linkuse as main transcript	c.5387C>T	p.Ser1796Phe	missense_variant	33/34

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC88A	ENST00000436346.7 linkuse as main transcript	c.5612C>T	p.Ser1871Phe	missense_variant	32/33	5	NM_001365480.1	A1	Q3V6T2-1
	ENST00000625718.2 linkuse as main transcript	n.85+9281G>A		intron_variant, non_coding_transcript_variant		5

Frequencies

GnomAD3 genomes

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

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:

0.000118

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000201

AC:

AN:

248964

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134702

show subpopulations

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 SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000355

Gnomad OTH exome

AF:

0.000165

GnomAD4 exome

AF:

0.000120

AC:

174

AN:

1453998

Hom.:

Cov.:

AF XY:

0.000112

AC XY:

AN XY:

723790

show subpopulations

Gnomad4 AFR exome

AF:

0.0000603

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:

0.000142

Gnomad4 OTH exome

AF:

0.000250

GnomAD4 genome

AF:

0.0000526

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

AN XY:

74348

show subpopulations

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:

0.000118

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000434

Hom.:

Bravo

AF:

0.0000529

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 07, 2022

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: "Not Available"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C65"). ClinVar contains an entry for this variant (Variation ID: 1477191). This variant has not been reported in the literature in individuals affected with CCDC88A-related conditions. This variant is present in population databases (rs200026991, gnomAD 0.006%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 1870 of the CCDC88A protein (p.Ser1870Phe). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.30

BayesDel_addAF

Benign

-0.043

BayesDel_noAF

Benign

-0.17

Cadd

Pathogenic

Dann

Uncertain

0.99

Eigen

Uncertain

0.58

Eigen_PC

Pathogenic

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

D;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Benign

0.012

MetaRNN

Benign

0.34

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-0.56

MutationTaster

Benign

0.94

D;D;D;D;N

PrimateAI

Uncertain

0.61

PROVEAN

Benign

-2.2

N;N;.;.;.;N;.;.;.;N;.;.

REVEL

Uncertain

0.32

Sift

Pathogenic

0.0

D;D;.;.;.;D;.;.;.;D;.;.

Sift4G

Pathogenic

0.0

D;D;.;.;.;D;.;.;.;D;.;.

Polyphen

1.0

D;D;D;.;.;.;.;.;.;.;.;.

Vest4

0.53

MVP

0.39

MPC

0.20

ClinPred

0.47

GERP RS

5.9

Varity_R

0.34

gMVP

0.45

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over