rs78877829

chr12-48918757-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_033124.5(CCDC65):c.880C>T(p.Arg294Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0513 in 1,613,972 control chromosomes in the GnomAD database, including 2,609 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R294H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.043 (209 hom., cov: 32)
  • Exomes 𝑓: 0.052 (2400 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.83

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017585754).
• BP6: Variant 12-48918757-C-T is Benign according to our data. Variant chr12-48918757-C-T is described in ClinVar as [Benign]. Clinvar id is 262221.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48918757-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0598 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5	c.880C>T	p.Arg294Cys	missense_variant	6/8	ENST00000320516.5
CCDC65	NM_001286957.2	c.451C>T	p.Arg151Cys	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5	c.880C>T	p.Arg294Cys	missense_variant	6/8	1	NM_033124.5	P2

Frequencies

GnomAD3 genomes AF: 0.0428 AC: 6513 AN: 152024 Hom.: 209 Cov.: 32

Gnomad AFR AF: 0.0105

Gnomad AMI AF: 0.0570

Gnomad AMR AF: 0.0332

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0106

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0613

Gnomad OTH AF: 0.0340

GnomAD3 exomes AF: 0.0415 AC: 10442 AN: 251482 Hom.: 338 AF XY: 0.0419 AC XY: 5700 AN XY: 135916

Gnomad AFR exome AF: 0.00769

Gnomad AMR exome AF: 0.0178

Gnomad ASJ exome AF: 0.0188

Gnomad EAS exome AF: 0.00147

Gnomad SAS exome AF: 0.0120

Gnomad FIN exome AF: 0.0995

Gnomad NFE exome AF: 0.0590

Gnomad OTH exome AF: 0.0414

GnomAD4 exome AF: 0.0522 AC: 76358 AN: 1461830 Hom.: 2400 Cov.: 33 AF XY: 0.0511 AC XY: 37157 AN XY: 727222

Gnomad4 AFR exome AF: 0.00738

Gnomad4 AMR exome AF: 0.0196

Gnomad4 ASJ exome AF: 0.0197

Gnomad4 EAS exome AF: 0.000605

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0981

Gnomad4 NFE exome AF: 0.0591

Gnomad4 OTH exome AF: 0.0448

GnomAD4 genome AF: 0.0428 AC: 6511 AN: 152142 Hom.: 209 Cov.: 32 AF XY: 0.0446 AC XY: 3320 AN XY: 74364

Gnomad4 AFR AF: 0.0105

Gnomad4 AMR AF: 0.0332

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0102

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.0613

Gnomad4 OTH AF: 0.0336

Alfa AF: 0.0508 Hom.: 409

Bravo AF: 0.0346

TwinsUK AF: 0.0591 AC: 219

ALSPAC AF: 0.0607 AC: 234

ESP6500AA AF: 0.0109 AC: 48

ESP6500EA AF: 0.0555 AC: 477

ExAC AF: 0.0413 AC: 5008

Asia WGS AF: 0.00606 AC: 21 AN: 3478

EpiCase AF: 0.0534

EpiControl AF: 0.0520

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Primary ciliary dyskinesia 27 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 24, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.27
Cadd	Pathogenic	26
Dann	Pathogenic	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Benign	0.79	T;T;T
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-0.89	T
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	.;.;D
Vest4		0.26
MPC		0.37
ClinPred		0.026	T
GERP RS		4.7
Varity_R		0.21
gMVP		0.31

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs78877829; hg19: chr12-49312540; COSMIC: COSV56740449; COSMIC: COSV56740449;