chr16-724395-G-A

Variant names:

• chr16-724395-G-A
• rs772096201
• NM_001378030.1:c.880C>T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001378030.1(CCDC78):​c.880C>T​(p.Arg294Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000993 in 1,611,526 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000055 (0 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.00900

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 Likely_benign. Variant got -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37268162).
• BS2: High AC in GnomAd4 at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC78	NM_001378030.1	c.880C>T	p.Arg294Trp	missense_variant	Exon 9 of 14	ENST00000345165.10	NP_001364959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC78	ENST00000345165.10	c.880C>T	p.Arg294Trp	missense_variant	Exon 9 of 14	5	NM_001378030.1	ENSP00000316851.5

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000814 AC: 2 AN: 245710 Hom.: 0 AF XY: 0.0000150 AC XY: 2 AN XY: 133768

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000550

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000548 AC: 8 AN: 1459202 Hom.: 0 Cov.: 35 AF XY: 0.0000110 AC XY: 8 AN XY: 725952

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74478

Gnomad4 AFR AF: 0.0000481

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: 0.0000147

Gnomad4 OTH AF: 0.00237

Bravo AF: 0.0000302

ExAC AF: 0.00000825 AC: 1

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Congenital myopathy with internal nuclei and atypical cores Uncertain:1

Oct 03, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 294 of the CCDC78 protein (p.Arg294Trp). This variant is present in population databases (rs772096201, gnomAD 0.006%). This variant has not been reported in the literature in individuals affected with CCDC78-related conditions. ClinVar contains an entry for this variant (Variation ID: 568175). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CCDC78 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.38
CADD	Pathogenic	28
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.13	T
Eigen	Benign	0.17
Eigen_PC	Benign	0.089
FATHMM_MKL	Benign	0.50	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.062	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M
PrimateAI	Benign	0.33	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.13
Sift	Uncertain	0.022	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.52
MutPred		0.37		Loss of disorder (P = 4e-04);
MVP		0.28
MPC		0.38
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.12
gMVP		0.13

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

Other links and lift over

dbSNP: rs772096201; hg19: chr16-774395;