rs142129985

chr16-725084-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001378030.1(CCDC78):c.554C>T(p.Thr185Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000496 in 1,612,690 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. T185T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000053 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000049 (0 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.239

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.026171654).
• BS2: High AC in GnomAd at 8 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC78	NM_001378030.1	c.554C>T	p.Thr185Met	missense_variant	6/14	ENST00000345165.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC78	ENST00000345165.10	c.554C>T	p.Thr185Met	missense_variant	6/14	5	NM_001378030.1	A2

Frequencies

GnomAD3 genomes AF: 0.0000526 AC: 8 AN: 152174 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000881 AC: 22 AN: 249620 Hom.: 0 AF XY: 0.0000959 AC XY: 13 AN XY: 135548

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000218

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000623

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000493 AC: 72 AN: 1460398 Hom.: 0 Cov.: 37 AF XY: 0.0000496 AC XY: 36 AN XY: 726472

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000525 AC: 8 AN: 152292 Hom.: 0 Cov.: 34 AF XY: 0.0000806 AC XY: 6 AN XY: 74470

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.0000592 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.000455 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000825 AC: 10

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.554C>T (p.T185M) alteration is located in exon 6 (coding exon 6) of the CCDC78 gene. This alteration results from a C to T substitution at nucleotide position 554, causing the threonine (T) at amino acid position 185 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myopathy with internal nuclei and atypical cores Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

This sequence change replaces threonine, which is neutral and polar, with methionine, which is neutral and non-polar, at codon 185 of the CCDC78 protein (p.Thr185Met). This variant is present in population databases (rs142129985, gnomAD 0.03%). 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: 540470). 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 with a negative predictive value of 80%. 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	0.090
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	7.2
Dann	Benign	0.86
DEOGEN2	Benign	0.072	T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.4
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.63	T;T
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.026	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-2.3	N;.
REVEL	Benign	0.017
Sift	Benign	0.15	T;.
Sift4G	Benign	0.073	T;.
Polyphen		0.070	B;.
Vest4		0.20
MVP		0.030
MPC		0.086
ClinPred		0.0052	T
GERP RS		-2.8
Varity_R		0.023
gMVP		0.059

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: rs142129985; hg19: chr16-775084; COSMIC: COSV52400743; COSMIC: COSV52400743;