rs145274257

Positions:

• chr16-725464-C-A
• chr16-725464-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378030.1(CCDC78):​c.384G>T​(p.Glu128Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000321 in 1,612,778 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. E128E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0017 (1 hom., cov: 34)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications B:4
• Conservation: PhyloP100: -0.121

Genes affected

CCDC78 (HGNC:14153): (coiled-coil domain containing 78) Involved in de novo centriole assembly involved in multi-ciliated epithelial cell differentiation and skeletal muscle contraction. Located in several cellular components, including centriole; deuterosome; and sarcolemma. Implicated in centronuclear myopathy 4. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043239594).
• BP6: Variant 16-725464-C-A is Benign according to our data. Variant chr16-725464-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447008.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Likely_benign=2}.
• BS2: High AC in GnomAd4 at 252 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC78	NM_001378030.1	c.384G>T	p.Glu128Asp	missense_variant	4/14	ENST00000345165.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC78	ENST00000345165.10	c.384G>T	p.Glu128Asp	missense_variant	4/14	5	NM_001378030.1	A2

Frequencies

GnomAD3 genomes AF: 0.00165 AC: 251 AN: 152236 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.00543

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.000497 AC: 124 AN: 249610 Hom.: 0 AF XY: 0.000325 AC XY: 44 AN XY: 135464

Gnomad AFR exome AF: 0.00591

Gnomad AMR exome AF: 0.000666

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: 0.00000890

Gnomad OTH exome AF: 0.000820

GnomAD4 exome AF: 0.000182 AC: 266 AN: 1460424 Hom.: 0 Cov.: 37 AF XY: 0.000172 AC XY: 125 AN XY: 726494

Gnomad4 AFR exome AF: 0.00594

Gnomad4 AMR exome AF: 0.000693

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: 0.0000135

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.00165 AC: 252 AN: 152354 Hom.: 1 Cov.: 34 AF XY: 0.00162 AC XY: 121 AN XY: 74504

Gnomad4 AFR AF: 0.00543

Gnomad4 AMR AF: 0.00104

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.000445 Hom.: 1

Bravo AF: 0.00214

ESP6500AA AF: 0.00661 AC: 29

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000569 AC: 69

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Oct 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 28, 2020	- -

Congenital myopathy with internal nuclei and atypical cores Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 25, 2024

- -

CCDC78-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 22, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	4.6
DANN	Benign	0.97
DEOGEN2	Benign	0.085	T
Eigen	Benign	-0.83
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.15	N
LIST_S2	Benign	0.48	T
MetaRNN	Benign	0.0043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.10
Sift	Benign	0.19	T
Sift4G	Benign	0.38	T
Polyphen		0.88	P
Vest4		0.11
MutPred		0.20		Gain of MoRF binding (P = 0.1239);
MVP		0.12
MPC		0.096
ClinPred		0.0056	T
GERP RS		-0.30
Varity_R		0.065
gMVP		0.070

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs145274257; hg19: chr16-775464;