16-725236-C-T

Variant names:

• chr16-725236-C-T
• rs138669350
• NM_001378030.1:c.492+1G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 2P and 12B. PVS1_Moderate BP6_Very_Strong BS2

The NM_001378030.1(CCDC78):​c.492+1G>A variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00205 in 1,608,404 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (1 hom., cov: 34)
  • Exomes 𝑓: 0.0021 (7 hom.)
• Consequence: CCDC78 NM_001378030.1 splice_donor, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.602
• Publications: 6 publications found

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]

CCDC78 Gene-Disease associations (from GenCC):

• congenital myopathy with internal nuclei and atypical cores

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• centronuclear myopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.040339705 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 16-725236-C-T is Benign according to our data. Variant chr16-725236-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 265074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 268 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378030.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	NM_001378030.1	MANE Select	c.492+1G>A		splice_donor intron	N/A	NP_001364959.1
	CCDC78	NM_001378033.1		c.40G>A	p.Val14Met	missense	Exon 4 of 10	NP_001364962.1
	CCDC78	NM_001031737.3		c.492+1G>A		splice_donor intron	N/A	NP_001026907.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	ENST00000345165.10	TSL:5 MANE Select	c.492+1G>A		splice_donor intron	N/A	ENSP00000316851.5
	CCDC78	ENST00000293889.10	TSL:1	c.492+1G>A		splice_donor intron	N/A	ENSP00000293889.6
	CCDC78	ENST00000439619.6	TSL:2	n.570G>A		non_coding_transcript_exon	Exon 5 of 7

Frequencies

GnomAD3 genomes AF: 0.00177 AC: 269 AN: 152182 Hom.: 1 Cov.: 34

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00876

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00173

Gnomad OTH AF: 0.00192

GnomAD2 exomes AF: 0.00229 AC: 563 AN: 245486 AF XY: 0.00211

Gnomad AFR exome AF: 0.000516

Gnomad AMR exome AF: 0.00371

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0000546

Gnomad FIN exome AF: 0.00943

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00266

GnomAD4 exome AF: 0.00208 AC: 3033 AN: 1456104 Hom.: 7 Cov.: 37 AF XY: 0.00201 AC XY: 1458 AN XY: 724606

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.00335 AC: 150 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.000842 AC: 22 AN: 26134

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86258

European-Finnish (FIN) AF: 0.0111 AC: 531 AN: 47762

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00194 AC: 2157 AN: 1111944

Other (OTH) AF: 0.00194 AC: 117 AN: 60342

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152300 Hom.: 1 Cov.: 34 AF XY: 0.00200 AC XY: 149 AN XY: 74468

African (AFR) AF: 0.000529 AC: 22 AN: 41566

American (AMR) AF: 0.00163 AC: 25 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00115 AC: 4 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4824

European-Finnish (FIN) AF: 0.00876 AC: 93 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00173 AC: 118 AN: 68016

Other (OTH) AF: 0.00142 AC: 3 AN: 2110

Alfa AF: 0.00143 Hom.: 0

Bravo AF: 0.00122

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00151 AC: 13

ExAC AF: 0.00239 AC: 290

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Sep 04, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 04, 2020

Athena Diagnostics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCDC78: BS1, BS2

Jun 16, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital myopathy with internal nuclei and atypical cores Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CCDC78-related disorder Benign:1

Mar 13, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	17
DANN	Benign	0.67
Eigen	Benign	0.070
Eigen_PC	Benign	-0.35
FATHMM_MKL	Benign	0.12	N
PhyloP100		-0.60
GERP RS		-0.34
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Benign	0.69
SpliceAI score (max)		0.70		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.70		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs138669350; hg19: chr16-775236;