rs143439721

Variant names:

• chr16-724735-C-G
• rs143439721
• NM_001378030.1:c.711G>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001378030.1(CCDC78):​c.711G>C​(p.Lys237Asn) 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 1,612,216 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 0.000046 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000050 (0 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.39
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.37027907).
• BS2: High AC in GnomAd4 at 7 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	NM_001378030.1	MANE Select	c.711G>C	p.Lys237Asn	missense	Exon 8 of 14	NP_001364959.1	H3BLT8
	CCDC78	NM_001031737.3		c.711G>C	p.Lys237Asn	missense	Exon 8 of 14	NP_001026907.2	A2IDD5-1
	CCDC78	NM_001378031.1		c.711G>C	p.Lys237Asn	missense	Exon 8 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.711G>C	p.Lys237Asn	missense	Exon 8 of 14	ENSP00000316851.5	H3BLT8
	CCDC78	ENST00000293889.10	TSL:1	c.711G>C	p.Lys237Asn	missense	Exon 8 of 14	ENSP00000293889.6	A2IDD5-1
	CCDC78	ENST00000947033.1		c.711G>C	p.Lys237Asn	missense	Exon 8 of 14	ENSP00000617092.1

Frequencies

GnomAD3 genomes AF: 0.0000460 AC: 7 AN: 152266 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: 0.000103

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000242 AC: 6 AN: 247436 AF XY: 0.0000297

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: 0.0000538

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000500 AC: 73 AN: 1459950 Hom.: 0 Cov.: 38 AF XY: 0.0000441 AC XY: 32 AN XY: 726228

African (AFR) AF: 0.00 AC: 0 AN: 33472

American (AMR) AF: 0.00 AC: 0 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.00 AC: 0 AN: 39686

South Asian (SAS) AF: 0.00 AC: 0 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51938

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

European-Non Finnish (NFE) AF: 0.0000603 AC: 67 AN: 1111820

Other (OTH) AF: 0.0000994 AC: 6 AN: 60332

GnomAD4 genome AF: 0.0000460 AC: 7 AN: 152266 Hom.: 0 Cov.: 34 AF XY: 0.0000538 AC XY: 4 AN XY: 74386

African (AFR) AF: 0.00 AC: 0 AN: 41466

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5206

South Asian (SAS) AF: 0.00 AC: 0 AN: 4838

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

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

European-Non Finnish (NFE) AF: 0.000103 AC: 7 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.0000676 Hom.: 0

Bravo AF: 0.0000340

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.00000829 AC: 1

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.32	T
Eigen	Benign	-0.27
Eigen_PC	Benign	-0.29
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.061	D
MetaRNN	Benign	0.37	T
MetaSVM	Benign	-0.77	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		2.4
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.18
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.49
MutPred		0.22		Gain of ubiquitination at K240 (P = 0.0379)
MVP		0.18
MPC		0.41
ClinPred		0.82	D
GERP RS		3.5
Varity_R		0.78
gMVP		0.31
Mutation Taster		=89/11	polymorphism

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

Other links and lift over

dbSNP: rs143439721; hg19: chr16-774735;