rs866658813

chr12-48921268-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033124.5(CCDC65):c.1280A>G(p.Asp427Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000483 in 1,614,258 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000050 (1 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.48

Genes affected

CCDC65 (HGNC:29937): (coiled-coil domain containing 65) This gene encodes a sperm tail protein that is highly expressed in adult testis, spermatocytes and spermatids. The protein plays a critical role in the assembly of the nexin-dynein regulatory complex. Mutations in this gene result in primary ciliary dyskinesia. [provided by RefSeq, Nov 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06944871).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5	c.1280A>G	p.Asp427Gly	missense_variant	8/8	ENST00000320516.5
CCDC65	NM_001286957.2	c.851A>G	p.Asp284Gly	missense_variant	8/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5	c.1280A>G	p.Asp427Gly	missense_variant	8/8	1	NM_033124.5	P2
CCDC65	ENST00000266984.9	c.1280A>G	p.Asp427Gly	missense_variant	8/9	5		A2
CCDC65	ENST00000552942.5	c.971A>G	p.Asp324Gly	missense_variant	6/6	5
CCDC65	ENST00000547861.5	c.*1111A>G		3_prime_UTR_variant, NMD_transcript_variant	8/8	2

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152246 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000795 AC: 2 AN: 251480 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135920

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000176

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000499 AC: 73 AN: 1461894 Hom.: 1 Cov.: 37 AF XY: 0.0000605 AC XY: 44 AN XY: 727248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000405

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152364 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74516

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000501 Hom.: 0

Bravo AF: 0.0000113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 27 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Baylor Genetics	Jul 16, 2019	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 16, 2022	This sequence change replaces aspartic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 427 of the CCDC65 protein (p.Asp427Gly). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with CCDC65-related conditions. ClinVar contains an entry for this variant (Variation ID: 411131). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.47
Cadd	Benign	16
Dann	Benign	0.97
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.59
FATHMM_MKL	Benign	0.14	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.0070	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.94	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.20	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.095	.;.;B
Vest4		0.12
MutPred		0.25		Gain of catalytic residue at L432 (P = 0.0082);.;Gain of catalytic residue at L432 (P = 0.0082);
MVP		0.014
MPC		0.061
ClinPred		0.16	T
GERP RS		1.7
Varity_R		0.091
gMVP		0.20

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

Publications

LitVar

Other links and lift over

dbSNP: rs866658813; hg19: chr12-49315051; COSMIC: COSV99872887; COSMIC: COSV99872887;