3-56563855-A-G

Variant names:

• chr3-56563855-A-G
• rs754517222
• NM_001141947.3:c.274A>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001141947.3(CCDC66):​c.274A>G​(p.Thr92Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict 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. T92P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC66 NM_001141947.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.182
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04488349).

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.274A>G	p.Thr92Ala	missense	Exon 4 of 18	NP_001135419.1	A2RUB6-1
	CCDC66	NM_001353147.1		c.274A>G	p.Thr92Ala	missense	Exon 4 of 18	NP_001340076.1
	CCDC66	NM_001353148.1		c.274A>G	p.Thr92Ala	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.274A>G	p.Thr92Ala	missense	Exon 4 of 18	ENSP00000378167.3	A2RUB6-1
	CCDC66	ENST00000326595.11	TSL:1	c.172A>G	p.Thr58Ala	missense	Exon 4 of 18	ENSP00000326050.7	A2RUB6-3
	CCDC66	ENST00000341455.10	TSL:1	n.274A>G		non_coding_transcript_exon	Exon 4 of 18	ENSP00000343840.6	F8WCY0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

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	0.071
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	10
DANN	Benign	0.95
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.092	N
LIST_S2	Benign	0.59	T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.7	L
PhyloP100		-0.18
PrimateAI	Benign	0.22	T
PROVEAN	Benign	-1.0	N
REVEL	Benign	0.025
Sift	Benign	0.15	T
Sift4G	Benign	0.30	T
Polyphen		0.0010	B
Vest4		0.050
MutPred		0.14		Loss of phosphorylation at T92 (P = 0.0221)
MVP		0.14
MPC		0.016
ClinPred		0.036	T
GERP RS		2.0
Varity_R		0.056
gMVP		0.097
Mutation Taster		=96/4	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

dbSNP: rs754517222; hg19: chr3-56597883;