3-56563853-C-T

Variant names:

• chr3-56563853-C-T
• rs2065443703
• NM_001141947.3:c.272C>T

Variant summary

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

The NM_001141947.3(CCDC66):​c.272C>T​(p.Ser91Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,434,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S91Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: CCDC66 NM_001141947.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.60
• 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=0.21784371).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001141947.3. 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.272C>T	p.Ser91Phe	missense	Exon 4 of 18	NP_001135419.1	A2RUB6-1
	CCDC66	NM_001353147.1		c.272C>T	p.Ser91Phe	missense	Exon 4 of 18	NP_001340076.1
	CCDC66	NM_001353148.1		c.272C>T	p.Ser91Phe	missense	Exon 4 of 18	NP_001340077.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC66	ENST00000394672.8	TSL:1 MANE Select	c.272C>T	p.Ser91Phe	missense	Exon 4 of 18	ENSP00000378167.3	A2RUB6-1
	CCDC66	ENST00000326595.11	TSL:1	c.170C>T	p.Ser57Phe	missense	Exon 4 of 18	ENSP00000326050.7	A2RUB6-3
	CCDC66	ENST00000341455.10	TSL:1	n.272C>T		non_coding_transcript_exon	Exon 4 of 18	ENSP00000343840.6	F8WCY0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.97e-7 AC: 1 AN: 1434778 Hom.: 0 Cov.: 33 AF XY: 0.00000141 AC XY: 1 AN XY: 711464

⚠️ 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: 32454

American (AMR) AF: 0.00 AC: 0 AN: 40724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25676

East Asian (EAS) AF: 0.00 AC: 0 AN: 38204

South Asian (SAS) AF: 0.00 AC: 0 AN: 83162

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52208

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5734

European-Non Finnish (NFE) AF: 9.11e-7 AC: 1 AN: 1097186

Other (OTH) AF: 0.00 AC: 0 AN: 59430

⚠️ 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

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.028	T
Eigen	Benign	0.059
Eigen_PC	Benign	0.15
FATHMM_MKL	Benign	0.11	N
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.22	T
MetaSVM	Pathogenic	0.83	D
MutationAssessor	Benign	0.90	L
PhyloP100		1.6
PrimateAI	Benign	0.28	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.36
Sift	Benign	0.088	T
Sift4G	Benign	0.063	T
Polyphen		0.73	P
Vest4		0.19
MutPred		0.17		Loss of ubiquitination at K93 (P = 0.045)
MVP		0.60
MPC		0.024
ClinPred		0.56	D
GERP RS		4.9
Varity_R		0.098
gMVP		0.076
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs2065443703; hg19: chr3-56597881;