NM_001378030.1:c.1190G>C

Variant names:

• chr16-723105-C-G
• rs150304459
• NM_001378030.1:c.1190G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001378030.1(CCDC78):​c.1190G>C​(p.Arg397Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,236 control chromosomes in the GnomAD database, with no homozygous occurrence. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R397C) has been classified as Likely benign.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 34)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -4.07
• Publications: 4 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• centronuclear myopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	NM_001378030.1	MANE Select	c.1190G>C	p.Arg397Pro	missense	Exon 12 of 14	NP_001364959.1	H3BLT8
	CCDC78	NM_001031737.3		c.1190G>C	p.Arg397Pro	missense	Exon 12 of 14	NP_001026907.2	A2IDD5-1
	CCDC78	NM_001378031.1		c.1010G>C	p.Arg337Pro	missense	Exon 10 of 12	NP_001364960.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	ENST00000345165.10	TSL:5 MANE Select	c.1190G>C	p.Arg397Pro	missense	Exon 12 of 14	ENSP00000316851.5	H3BLT8
	CCDC78	ENST00000293889.10	TSL:1	c.1190G>C	p.Arg397Pro	missense	Exon 12 of 14	ENSP00000293889.6	A2IDD5-1
	CCDC78	ENST00000947033.1		c.1190G>C	p.Arg397Pro	missense	Exon 12 of 14	ENSP00000617092.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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

GnomAD4 exome Cov.: 34

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152236 Hom.: 0 Cov.: 34 AF XY: 0.0000134 AC XY: 1 AN XY: 74380

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41468

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5202

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68026

Other (OTH) AF: 0.00 AC: 0 AN: 2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Congenital myopathy with internal nuclei and atypical cores (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.36
BayesDel_addAF	Benign	-0.063	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	15
DANN	Benign	0.84
DEOGEN2	Benign	0.087	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.47	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.81	L
PhyloP100		-4.1
PrimateAI	Benign	0.20	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.17
Sift	Benign	0.054	T
Sift4G	Uncertain	0.010	D
Polyphen		0.99	D
Vest4		0.55
MutPred		0.33		Loss of MoRF binding (P = 6e-04)
MVP		0.085
MPC		0.41
ClinPred		0.79	D
GERP RS		-1.4
Varity_R		0.36
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs150304459; hg19: chr16-773105;