NM_024296.5:c.281G>A

Variant names:

• chr1-32203995-G-A
• rs200163249
• NM_024296.5:c.281G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_024296.5(CCDC28B):​c.281G>A​(p.Gly94Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000562 in 1,422,374 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: CCDC28B NM_024296.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.75
• Publications: 2 publications found

Genes affected

CCDC28B (HGNC:28163): (coiled-coil domain containing 28B) The product of this gene localizes to centrosomes and basal bodies. The protein colocalizes with several proteins associated with Bardet-Biedl syndrome (BBS) and participates in the regulation of cilia development. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2014]

CCDC28B Gene-Disease associations (from GenCC):

• Bardet-Biedl syndrome 1

  Inheritance: AR Classification: NO_KNOWN Submitted by: Ambry Genetics

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.839

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024296.5. 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
	CCDC28B	NM_024296.5	MANE Select	c.281G>A	p.Gly94Glu	missense	Exon 3 of 6	NP_077272.2	Q9BUN5-1
	CCDC28B	NM_001301011.2		c.281G>A	p.Gly94Glu	missense	Exon 3 of 5	NP_001287940.1	Q9BUN5-3
	CCDC28B	NM_001437632.1		c.281G>A	p.Gly94Glu	missense	Exon 3 of 5	NP_001424561.1	A0A7P0TB33

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC28B	ENST00000373602.10	TSL:1 MANE Select	c.281G>A	p.Gly94Glu	missense	Exon 3 of 6	ENSP00000362704.5	Q9BUN5-1
	CCDC28B	ENST00000421922.6	TSL:1	c.281G>A	p.Gly94Glu	missense	Exon 3 of 5	ENSP00000413017.2	Q9BUN5-3
	CCDC28B	ENST00000868525.1		c.281G>A	p.Gly94Glu	missense	Exon 2 of 5	ENSP00000538584.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000930 AC: 2 AN: 214948 AF XY: 0.0000174

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000101

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000562 AC: 8 AN: 1422374 Hom.: 0 Cov.: 32 AF XY: 0.00000568 AC XY: 4 AN XY: 704284

African (AFR) AF: 0.0000311 AC: 1 AN: 32142

American (AMR) AF: 0.0000258 AC: 1 AN: 38750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23372

East Asian (EAS) AF: 0.00 AC: 0 AN: 39280

South Asian (SAS) AF: 0.00 AC: 0 AN: 79572

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52044

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5564

European-Non Finnish (NFE) AF: 0.00000549 AC: 6 AN: 1092894

Other (OTH) AF: 0.00 AC: 0 AN: 58756

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ExAC AF: 0.00000825 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.023	T
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.35	T
MutationAssessor	Uncertain	2.4	M
PhyloP100		9.7
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.58
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.98
MutPred		0.45		Loss of catalytic residue at E92 (P = 0.1447)
MVP		0.63
MPC		1.2
ClinPred		0.98	D
GERP RS		4.6
Varity_R		0.88
gMVP		0.79
Mutation Taster		=45/55	disease causing

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: rs200163249; hg19: chr1-32669596;