12-48914501-A-G

Position:

chr12-48914501-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_033124.5(CCDC65):c.398A>G(p.His133Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.371 in 1,613,544 control chromosomes in the GnomAD database, including 115,383 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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. H133Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.33 ( 9159 hom., cov: 32)

Exomes 𝑓: 0.38 ( 106224 hom. )

Consequence

CCDC65
NM_033124.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 3.33

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.7789006E-4).

BP6

Variant 12-48914501-A-G is Benign according to our data. Variant chr12-48914501-A-G is described in ClinVar as [Benign]. Clinvar id is 402501.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC65	NM_033124.5 linkuse as main transcript	c.398A>G	p.His133Arg	missense_variant	3/8	ENST00000320516.5
CCDC65	NM_001286957.2 linkuse as main transcript	c.-32A>G		5_prime_UTR_variant	3/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC65	ENST00000320516.5 linkuse as main transcript	c.398A>G	p.His133Arg	missense_variant	3/8	1	NM_033124.5	P2	Q8IXS2-1
CCDC65	ENST00000266984.9 linkuse as main transcript	c.398A>G	p.His133Arg	missense_variant	3/9	5		A2	Q8IXS2-2
CCDC65	ENST00000552942.5 linkuse as main transcript	c.301-3774A>G		intron_variant		5
CCDC65	ENST00000547861.5 linkuse as main transcript	c.*229A>G		3_prime_UTR_variant, NMD_transcript_variant	3/8	2

Frequencies

GnomAD3 genomes

AF:

0.327

AC:

49763

AN:

151988

Hom.:

9150

Cov.:

show subpopulations

Gnomad AFR

AF:

0.161

Gnomad AMI

AF:

0.433

Gnomad AMR

AF:

0.476

Gnomad ASJ

AF:

0.435

Gnomad EAS

AF:

0.471

Gnomad SAS

AF:

0.222

Gnomad FIN

AF:

0.372

Gnomad MID

AF:

0.395

Gnomad NFE

AF:

0.377

Gnomad OTH

AF:

0.361

GnomAD3 exomes

AF:

0.382

AC:

96026

AN:

251288

Hom.:

19998

AF XY:

0.374

AC XY:

50766

AN XY:

135826

show subpopulations

Gnomad AFR exome

AF:

0.153

Gnomad AMR exome

AF:

0.553

Gnomad ASJ exome

AF:

0.437

Gnomad EAS exome

AF:

0.469

Gnomad SAS exome

AF:

0.220

Gnomad FIN exome

AF:

0.383

Gnomad NFE exome

AF:

0.387

Gnomad OTH exome

AF:

0.389

GnomAD4 exome

AF:

0.375

AC:

548147

AN:

1461438

Hom.:

106224

Cov.:

AF XY:

0.372

AC XY:

270117

AN XY:

727052

show subpopulations

Gnomad4 AFR exome

AF:

0.155

Gnomad4 AMR exome

AF:

0.538

Gnomad4 ASJ exome

AF:

0.432

Gnomad4 EAS exome

AF:

0.477

Gnomad4 SAS exome

AF:

0.224

Gnomad4 FIN exome

AF:

0.387

Gnomad4 NFE exome

AF:

0.382

Gnomad4 OTH exome

AF:

0.367

GnomAD4 genome

AF:

0.327

AC:

49784

AN:

152106

Hom.:

9159

Cov.:

AF XY:

0.331

AC XY:

24601

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.161

Gnomad4 AMR

AF:

0.476

Gnomad4 ASJ

AF:

0.435

Gnomad4 EAS

AF:

0.472

Gnomad4 SAS

AF:

0.221

Gnomad4 FIN

AF:

0.372

Gnomad4 NFE

AF:

0.377

Gnomad4 OTH

AF:

0.365

Alfa

AF:

0.367

Hom.:

10261

Bravo

AF:

0.338

TwinsUK

AF:

0.374

AC:

1386

ALSPAC

AF:

0.375

AC:

1445

ESP6500AA

AF:

0.161

AC:

711

ESP6500EA

AF:

0.382

AC:

3288

ExAC

AF:

0.370

AC:

44889

Asia WGS

AF:

0.360

AC:

1250

AN:

3478

EpiCase

AF:

0.389

EpiControl

AF:

0.392

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 27

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 10, 2018	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 29, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.79

BayesDel_noAF

Benign

-0.76

CADD

Benign

DANN

Benign

0.46

DEOGEN2

Benign

0.00032

.;T

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.0092

LIST_S2

Benign

0.26

T;T

MetaRNN

Benign

0.00018

T;T

MetaSVM

Benign

-0.90

MutationTaster

Benign

1.0

P;P;P

PrimateAI

Benign

0.30

PROVEAN

Benign

0.56

N;N

REVEL

Benign

0.086

Sift

Benign

0.57

T;T

Sift4G

Benign

0.51

T;T

Polyphen

0.0

.;B

Vest4

0.018

MPC

0.057

ClinPred

0.0078

GERP RS

0.87

Varity_R

0.026

gMVP

0.031

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

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