3-56558904-C-G

Variant names:

• chr3-56558904-C-G
• ENST00000326595.11:c.-33C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001353151.1(CCDC66):​c.-4C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,391,404 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: not found (cov: 33)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: CCDC66 NM_001353151.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.244
• Publications: 0 publications found

Genes affected

CCDC66 (HGNC:27709): (coiled-coil domain containing 66) Enables microtubule binding activity. Involved in cilium assembly; microtubule bundle formation; and regulation of protein localization to cilium. Located in several cellular components, including Flemming body; microtubule cytoskeleton; and photoreceptor inner segment. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21467191).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353151.1. 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
	CCDC66	NM_001141947.3	MANE Select	c.70C>G	p.Pro24Ala	missense	Exon 2 of 18	NP_001135419.1	A2RUB6-1
	CCDC66	NM_001353151.1		c.-4C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 17	NP_001340080.1
	CCDC66	NM_001012506.5		c.-33C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	NP_001012524.4	A2RUB6-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC66	ENST00000326595.11	TSL:1	c.-33C>G		5_prime_UTR_premature_start_codon_gain	Exon 2 of 18	ENSP00000326050.7	A2RUB6-3
	CCDC66	ENST00000394672.8	TSL:1 MANE Select	c.70C>G	p.Pro24Ala	missense	Exon 2 of 18	ENSP00000378167.3	A2RUB6-1
	CCDC66	ENST00000326595.11	TSL:1	c.-33C>G		5_prime_UTR	Exon 2 of 18	ENSP00000326050.7	A2RUB6-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.19e-7 AC: 1 AN: 1391404 Hom.: 0 Cov.: 27 AF XY: 0.00000146 AC XY: 1 AN XY: 686646

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31422

American (AMR) AF: 0.00 AC: 0 AN: 35442

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25076

East Asian (EAS) AF: 0.00 AC: 0 AN: 35528

South Asian (SAS) AF: 0.00 AC: 0 AN: 78582

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5622

European-Non Finnish (NFE) AF: 9.32e-7 AC: 1 AN: 1073034

Other (OTH) AF: 0.00 AC: 0 AN: 57694

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.034	T
Eigen	Benign	0.047
Eigen_PC	Benign	0.20
FATHMM_MKL	Benign	0.65	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	0.79	D
MutationAssessor	Benign	2.0	M
PhyloP100		0.24
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.41
Sift	Benign	0.25	T
Sift4G	Benign	0.71	T
Polyphen		0.21	B
Vest4		0.13
MutPred		0.36		Gain of MoRF binding (P = 0.0436)
MVP		0.58
MPC		0.12
ClinPred		0.46	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.070
gMVP		0.12
Mutation Taster		=91/9	polymorphism

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

hg19: chr3-56592932;