Genetic Variant CFAP184:p.Arg185Lys (chr4-7042385-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153376.3(CFAP184):c.554G>A(p.Arg185Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,611,950 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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: 33)

Exomes 𝑓: 0.0000069 ( 0 hom. )

Consequence

CFAP184
NM_153376.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -4.65

Variant links:

Genes affected

CFAP184 (HGNC:26900): (cilia and flagella associated protein 184) Predicted to be involved in cilium assembly. Predicted to be active in axoneme and ciliary basal body. [provided by Alliance of Genome Resources, Apr 2022]

CFAP184 links:

TADA2B (HGNC:30781): (transcriptional adaptor 2B) TADA2B functions as a transcriptional adaptor protein that potentiates transcription through coordination of histone acetyltransferase (HAT) activity and by linking activation factors to basal transcriptional machinery (Barlev et al., 2003 [PubMed 12972612]).[supplied by OMIM, Apr 2010]

TADA2B links:

ENSG00000245748 (HGNC:):

ENSG00000245748 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.036684334).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CFAP184	NM_153376.3 link	c.554G>A	p.Arg185Lys	missense_variant	Exon 1 of 1	ENST00000310085.6	NP_699207.1	Q2M329
LOC100129931	NR_033828.1 link	n.696+2595G>A		intron_variant	Intron 2 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CCDC96	ENST00000310085.6 link	c.554G>A	p.Arg185Lys	missense_variant	Exon 1 of 1	6	NM_153376.3	ENSP00000309285.4	Q2M329
TADA2B	ENST00000506692.1 link	c.-7+299C>T		intron_variant	Intron 1 of 1	2		ENSP00000422398.1	D6RC20
ENSG00000245748	ENST00000500031.1 link	n.696+2595G>A		intron_variant	Intron 2 of 3	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152196

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000202

AC:

AN:

247348

Hom.:

AF XY:

0.0000149

AC XY:

AN XY:

134416

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:

0.0000449

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1459754

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

726188

show subpopulations

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:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74354

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:

0.0000147

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000594

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 12, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.554G>A (p.R185K) alteration is located in exon 1 (coding exon 1) of the CCDC96 gene. This alteration results from a G to A substitution at nucleotide position 554, causing the arginine (R) at amino acid position 185 to be replaced by a lysine (K). 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

Benign

0.068

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.047

DANN

Benign

0.79

DEOGEN2

Benign

0.0097

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.9

FATHMM_MKL

Benign

0.023

LIST_S2

Benign

0.22

M_CAP

Benign

0.0041

MetaRNN

Benign

0.037

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.22

PROVEAN

Benign

-0.25

REVEL

Benign

0.0050

Sift

Benign

0.27

Sift4G

Benign

0.93

Polyphen

0.0020

Vest4

0.044

MutPred

0.28

Gain of glycosylation at S182 (P = 0.0015);

MVP

0.014

ClinPred

0.11

GERP RS

-8.6

Varity_R

0.047

gMVP

0.10

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