rs117646559

Positions:

• chr12-48918898-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_033124.5(CCDC65):​c.1021G>T​(p.Asp341Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0113 in 1,610,524 control chromosomes in the GnomAD database, including 124 homozygotes. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D341G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0081 (7 hom., cov: 31)
  • Exomes 𝑓: 0.012 (117 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.610

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=0.0040610135).
• BP6: Variant 12-48918898-G-T is Benign according to our data. Variant chr12-48918898-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 416603.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-48918898-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00814 (1224/150326) while in subpopulation NFE AF= 0.0125 (844/67702). AF 95% confidence interval is 0.0118. There are 7 homozygotes in gnomad4. There are 580 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 7 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5	c.1021G>T	p.Asp341Tyr	missense_variant	6/8	ENST00000320516.5
CCDC65	NM_001286957.2	c.592G>T	p.Asp198Tyr	missense_variant	6/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5	c.1021G>T	p.Asp341Tyr	missense_variant	6/8	1	NM_033124.5	P2

Frequencies

GnomAD3 genomes AF: 0.00815 AC: 1225 AN: 150226 Hom.: 7 Cov.: 31

Gnomad AFR AF: 0.00254

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.00293

Gnomad ASJ AF: 0.0110

Gnomad EAS AF: 0.000205

Gnomad SAS AF: 0.00631

Gnomad FIN AF: 0.00508

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.00870

GnomAD3 exomes AF: 0.00752 AC: 1887 AN: 251054 Hom.: 10 AF XY: 0.00780 AC XY: 1058 AN XY: 135726

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00261

Gnomad ASJ exome AF: 0.0111

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00585

Gnomad FIN exome AF: 0.00467

Gnomad NFE exome AF: 0.0116

Gnomad OTH exome AF: 0.00750

GnomAD4 exome AF: 0.0117 AC: 17033 AN: 1460198 Hom.: 117 Cov.: 31 AF XY: 0.0115 AC XY: 8355 AN XY: 726540

Gnomad4 AFR exome AF: 0.00188

Gnomad4 AMR exome AF: 0.00286

Gnomad4 ASJ exome AF: 0.0101

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00653

Gnomad4 FIN exome AF: 0.00509

Gnomad4 NFE exome AF: 0.0136

Gnomad4 OTH exome AF: 0.00936

GnomAD4 genome AF: 0.00814 AC: 1224 AN: 150326 Hom.: 7 Cov.: 31 AF XY: 0.00790 AC XY: 580 AN XY: 73372

Gnomad4 AFR AF: 0.00253

Gnomad4 AMR AF: 0.00292

Gnomad4 ASJ AF: 0.0110

Gnomad4 EAS AF: 0.000206

Gnomad4 SAS AF: 0.00632

Gnomad4 FIN AF: 0.00508

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.00866

Alfa AF: 0.0114 Hom.: 19

Bravo AF: 0.00798

TwinsUK AF: 0.0127 AC: 47

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00227 AC: 10

ESP6500EA AF: 0.0149 AC: 128

ExAC AF: 0.00732 AC: 889

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 27 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Mar 03, 2022	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2022	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	CCDC65: BP4, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.45
CADD	Benign	20
DANN	Uncertain	0.99
Eigen	Benign	-0.089
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.75	T;T;T
MetaRNN	Benign	0.0041	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	D;N;N
PrimateAI	Benign	0.37	T
PROVEAN	Uncertain	-3.7	D;D;D
REVEL	Benign	0.065
Sift	Uncertain	0.020	D;D;D
Sift4G	Uncertain	0.019	D;D;D
Polyphen		0.95	.;.;P
Vest4		0.38
MVP		0.048
MPC		0.24
ClinPred		0.017	T
GERP RS		3.8
Varity_R		0.34
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs117646559; hg19: chr12-49312681;