chr3-56558871-T-G

Variant names:

• chr3-56558871-T-G
• rs992631263
• NM_001141947.3:c.37T>G

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.37T>G​(p.Leu13Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,549,676 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: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: CCDC66 NM_001141947.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.07
• 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=0.13488111).

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.37T>G	p.Leu13Val	missense	Exon 2 of 18	NP_001135419.1	A2RUB6-1
	CCDC66	NM_001353147.1		c.37T>G	p.Leu13Val	missense	Exon 2 of 18	NP_001340076.1
	CCDC66	NM_001353148.1		c.37T>G	p.Leu13Val	missense	Exon 2 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.37T>G	p.Leu13Val	missense	Exon 2 of 18	ENSP00000378167.3	A2RUB6-1
	CCDC66	ENST00000326595.11	TSL:1	c.-66T>G		5_prime_UTR	Exon 2 of 18	ENSP00000326050.7	A2RUB6-3
	CCDC66	ENST00000341455.10	TSL:1	n.37T>G		non_coding_transcript_exon	Exon 2 of 18	ENSP00000343840.6	F8WCY0

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000255 AC: 4 AN: 156588 AF XY: 0.0000241

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000163

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000286 AC: 4 AN: 1397464 Hom.: 0 Cov.: 28 AF XY: 0.00000290 AC XY: 2 AN XY: 689342

⚠️ 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: 31548

American (AMR) AF: 0.000112 AC: 4 AN: 35646

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25140

East Asian (EAS) AF: 0.00 AC: 0 AN: 35560

South Asian (SAS) AF: 0.00 AC: 0 AN: 79106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077770

Other (OTH) AF: 0.00 AC: 0 AN: 57934

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000100134), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152212 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74356

African (AFR) AF: 0.00 AC: 0 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68018

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

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	0.080
BayesDel_addAF	Benign	-0.021	T
BayesDel_noAF	Uncertain	0.0
CADD	Benign	15
DANN	Uncertain	1.0
DEOGEN2	Benign	0.013	T
Eigen	Benign	0.060
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.68	T
M_CAP	Uncertain	0.20	D
MetaRNN	Benign	0.13	T
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Benign	2.0	M
PhyloP100		1.1
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-0.49	N
REVEL	Uncertain	0.48
Sift	Benign	0.57	T
Sift4G	Benign	0.97	T
Polyphen		0.90	P
Vest4		0.12
MutPred		0.22		Gain of sheet (P = 0.039)
MVP		0.78
MPC		0.070
ClinPred		0.21	T
GERP RS		3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.036
gMVP		0.091
Mutation Taster		=95/5	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: rs992631263; hg19: chr3-56592899;