dbSNP rs372541279: CCDC65:p.Thr237Ile (chr12-48918375-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

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

The NM_033124.5(CCDC65):c.710C>T(p.Thr237Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0000378 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

CCDC65
NM_033124.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.32

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 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC65	NM_033124.5 link	c.710C>T	p.Thr237Ile	missense_variant	Exon 5 of 8	ENST00000320516.5	NP_149115.2	Q8IXS2-1
CCDC65	NM_001286957.2 link	c.281C>T	p.Thr94Ile	missense_variant	Exon 5 of 8		NP_001273886.1	B4DXQ7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5 link	c.710C>T	p.Thr237Ile	missense_variant	Exon 5 of 8	1	NM_033124.5	ENSP00000312706.4		Q8IXS2-1
ENSG00000272822	ENST00000398092.4 link	c.385-14467G>A		intron_variant	Intron 4 of 4	3		ENSP00000438507.1		F5H423

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.0000318

AC:

AN:

251456

Hom.:

AF XY:

0.0000368

AC XY:

AN XY:

135910

show subpopulations

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:

0.0000703

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000397

AC:

AN:

1461870

Hom.:

Cov.:

AF XY:

0.0000316

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000504

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152166

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74350

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000282

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 27

Uncertain:1

Aug 27, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces threonine with isoleucine at codon 237 of the CCDC65 protein (p.Thr237Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs372541279, ExAC 0.009%). This variant has not been reported in the literature in individuals affected with CCDC65-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). 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

Uncertain

0.50

BayesDel_addAF

Uncertain

0.033

BayesDel_noAF

Uncertain

0.0

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.15

.;.;T

Eigen

Pathogenic

0.75

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.82

T;T;T

M_CAP

Benign

0.011

MetaRNN

Uncertain

0.53

D;D;D

MetaSVM

Benign

-1.2

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.5

D;D;D

REVEL

Benign

0.28

Sift

Pathogenic

0.0

D;D;D

Sift4G

Uncertain

0.0050

D;T;D

Polyphen

1.0

.;.;D

Vest4

0.64

MVP

0.014

MPC

0.31

ClinPred

0.94

GERP RS

5.3

Varity_R

0.79

gMVP

0.74

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