16-725492-G-T

Variant names:

• chr16-725492-G-T
• rs750379614
• NM_001378030.1:c.356C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001378030.1(CCDC78):​c.356C>A​(p.Pro119His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,316 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 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. P119R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.364
• Publications: 0 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07989478).

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.356C>A	p.Pro119His	missense	Exon 4 of 14	NP_001364959.1	H3BLT8
	CCDC78	NM_001031737.3		c.356C>A	p.Pro119His	missense	Exon 4 of 14	NP_001026907.2	A2IDD5-1
	CCDC78	NM_001378031.1		c.356C>A	p.Pro119His	missense	Exon 4 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.356C>A	p.Pro119His	missense	Exon 4 of 14	ENSP00000316851.5	H3BLT8
	CCDC78	ENST00000293889.10	TSL:1	c.356C>A	p.Pro119His	missense	Exon 4 of 14	ENSP00000293889.6	A2IDD5-1
	CCDC78	ENST00000947033.1		c.356C>A	p.Pro119His	missense	Exon 4 of 14	ENSP00000617092.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD2 exomes AF: 0.00000401 AC: 1 AN: 249278 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000892

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460316 Hom.: 0 Cov.: 37 AF XY: 0.00 AC XY: 0 AN XY: 726450

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51948

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111956

Other (OTH) AF: 0.00 AC: 0 AN: 60376

GnomAD4 genome Cov.: 34

ExAC AF: 0.00000825 AC: 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	Benign	0.11
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.55
DANN	Benign	0.96
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.82
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.19	N
LIST_S2	Benign	0.37	T
M_CAP	Benign	0.034	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.6	L
PhyloP100		-0.36
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.092
Sift	Benign	0.55	T
Sift4G	Uncertain	0.033	D
Polyphen		0.98	D
Vest4		0.11
MutPred		0.17		Gain of sheet (P = 0.0827)
MVP		0.12
MPC		0.39
ClinPred		0.10	T
GERP RS		-4.2
Varity_R		0.061
gMVP		0.041

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

Other links and lift over

dbSNP: rs750379614; hg19: chr16-775492;