rs151189508

Positions:

• chr12-48917047-T-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033124.5(CCDC65):​c.548T>C​(p.Ile183Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000502 in 1,614,094 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00032 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00052 (0 hom.)
• Consequence: CCDC65 NM_033124.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.0770

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]

ENSG00000272822 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.014622778).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC65	NM_033124.5	c.548T>C	p.Ile183Thr	missense_variant	4/8	ENST00000320516.5	NP_149115.2
CCDC65	NM_001286957.2	c.119T>C	p.Ile40Thr	missense_variant	4/8		NP_001273886.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC65	ENST00000320516.5	c.548T>C	p.Ile183Thr	missense_variant	4/8	1	NM_033124.5	ENSP00000312706.4
ENSG00000272822	ENST00000398092.4	c.385-13139A>G		intron_variant		3		ENSP00000438507.1

Frequencies

GnomAD3 genomes AF: 0.000315 AC: 48 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000235 AC: 59 AN: 251450 Hom.: 0 AF XY: 0.000265 AC XY: 36 AN XY: 135902

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000434

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: 0.000378

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000522 AC: 763 AN: 1461836 Hom.: 0 Cov.: 32 AF XY: 0.000523 AC XY: 380 AN XY: 727230

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000470

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000639

Gnomad4 OTH exome AF: 0.000480

GnomAD4 genome AF: 0.000315 AC: 48 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.000309 AC XY: 23 AN XY: 74472

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000327

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000511 Hom.: 0

Bravo AF: 0.000400

TwinsUK AF: 0.000809 AC: 3

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000930 AC: 8

ExAC AF: 0.000247 AC: 30

EpiCase AF: 0.000545

EpiControl AF: 0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Primary ciliary dyskinesia 27 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 24, 2022

This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 183 of the CCDC65 protein (p.Ile183Thr). This variant is present in population databases (rs151189508, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with CCDC65-related conditions. ClinVar contains an entry for this variant (Variation ID: 241746). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	14
DANN	Benign	0.80
DEOGEN2	Benign	0.00086	.;T
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.60	T;T
M_CAP	Benign	0.0025	T
MetaRNN	Benign	0.015	T;T
MetaSVM	Benign	-0.89	T
PrimateAI	Benign	0.44	T
PROVEAN	Benign	1.9	N;N
REVEL	Benign	0.11
Sift	Benign	0.58	T;T
Sift4G	Benign	0.57	T;T
Polyphen		0.0	.;B
Vest4		0.14
MVP		0.014
MPC		0.059
ClinPred		0.023	T
GERP RS		4.2
Varity_R		0.043
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs151189508; hg19: chr12-49310830;