chr12-48904948-C-A

Position:

chr12-48904948-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_033124.5(CCDC65):c.135C>A(p.Asp45Glu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000558 in 1,596,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000059 ( 0 hom. )

Consequence

CCDC65
NM_033124.5 missense, splice_region

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.38

Variant links:

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]

CCDC65 links:

ENSG00000272822 (HGNC:):

ENSG00000272822 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.11999509).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC65	NM_033124.5 link	c.135C>A	p.Asp45Glu	missense_variant, splice_region_variant	2/8	ENST00000320516.5	NP_149115.2	Q8IXS2-1
CCDC65	NM_001286957.2 link	c.-279-16C>A		intron_variant			NP_001273886.1	B4DXQ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5 link	c.135C>A	p.Asp45Glu	missense_variant, splice_region_variant	2/8	1	NM_033124.5	ENSP00000312706.4		Q8IXS2-1
ENSG00000272822	ENST00000398092.4 link	c.385-1040G>T		intron_variant		3		ENSP00000438507.1		F5H423

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000412

AC:

AN:

242460

Hom.:

AF XY:

0.0000611

AC XY:

AN XY:

130936

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000927

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000551

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000543

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000589

AC:

AN:

1444144

Hom.:

Cov.:

AF XY:

0.0000614

AC XY:

AN XY:

716278

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000709

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000254

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000708

Gnomad4 OTH exome

AF:

0.0000504

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152182

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000678

Hom.:

Bravo

AF:

0.0000340

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 07, 2024

The c.135C>A (p.D45E) alteration is located in exon 2 (coding exon 2) of the CCDC65 gene. This alteration results from a C to A substitution at nucleotide position 135, causing the aspartic acid (D) at amino acid position 45 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Primary ciliary dyskinesia 27

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 15, 2021

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. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with CCDC65-related disease. This variant is present in population databases (rs184028693, ExAC 0.009%). This sequence change replaces aspartic acid with glutamic acid at codon 45 of the CCDC65 protein (p.Asp45Glu). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0039

.;.;T

Eigen

Benign

0.0057

Eigen_PC

Benign

0.056

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.76

T;T;T

M_CAP

Benign

0.0041

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-0.98

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-1.0

N;N;N

REVEL

Benign

0.11

Sift

Benign

0.39

T;T;T

Sift4G

Benign

0.74

T;T;T

Polyphen

0.93

.;.;P

Vest4

0.23

MVP

0.14

MPC

0.11

ClinPred

0.40

GERP RS

3.2

Varity_R

0.13

gMVP

0.10

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over