chr16-725878-G-C

Variant names:

• chr16-725878-G-C
• rs140761899
• NM_001378030.1:c.183C>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001378033.1(CCDC78):​c.-103C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,609,698 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00049 (0 hom., cov: 34)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CCDC78 NM_001378033.1 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.339
• Publications: 2 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: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.023700088).
• BP6: Variant 16-725878-G-C is Benign according to our data. Variant chr16-725878-G-C is described in ClinVar as Likely_benign. ClinVar VariationId is 573422.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 75 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001378033.1. 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.183C>G	p.Ile61Met	missense splice_region	Exon 3 of 14	NP_001364959.1	H3BLT8
	CCDC78	NM_001378033.1		c.-103C>G		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	NP_001364962.1
	CCDC78	NM_001031737.3		c.183C>G	p.Ile61Met	missense splice_region	Exon 3 of 14	NP_001026907.2	A2IDD5-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	ENST00000345165.10	TSL:5 MANE Select	c.183C>G	p.Ile61Met	missense splice_region	Exon 3 of 14	ENSP00000316851.5	H3BLT8
	CCDC78	ENST00000293889.10	TSL:1	c.183C>G	p.Ile61Met	missense splice_region	Exon 3 of 14	ENSP00000293889.6	A2IDD5-1
	CCDC78	ENST00000947033.1		c.183C>G	p.Ile61Met	missense splice_region	Exon 3 of 14	ENSP00000617092.1

Frequencies

GnomAD3 genomes AF: 0.000493 AC: 75 AN: 152232 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00135

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000327

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000211 AC: 51 AN: 241306 AF XY: 0.000153

Gnomad AFR exome AF: 0.00133

Gnomad AMR exome AF: 0.000296

Gnomad ASJ exome AF: 0.000824

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000736

Gnomad OTH exome AF: 0.000843

GnomAD4 exome AF: 0.000132 AC: 193 AN: 1457348 Hom.: 0 Cov.: 37 AF XY: 0.000127 AC XY: 92 AN XY: 724524

African (AFR) AF: 0.000868 AC: 29 AN: 33400

American (AMR) AF: 0.000316 AC: 14 AN: 44254

Ashkenazi Jewish (ASJ) AF: 0.00100 AC: 26 AN: 25950

East Asian (EAS) AF: 0.00 AC: 0 AN: 39648

South Asian (SAS) AF: 0.00 AC: 0 AN: 85394

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52684

Middle Eastern (MID) AF: 0.000521 AC: 3 AN: 5760

European-Non Finnish (NFE) AF: 0.0000955 AC: 106 AN: 1110026

Other (OTH) AF: 0.000249 AC: 15 AN: 60232

GnomAD4 genome AF: 0.000492 AC: 75 AN: 152350 Hom.: 0 Cov.: 34 AF XY: 0.000443 AC XY: 33 AN XY: 74504

African (AFR) AF: 0.00135 AC: 56 AN: 41586

American (AMR) AF: 0.000327 AC: 5 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10632

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

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68026

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000246 Hom.: 0

Bravo AF: 0.000495

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00160 AC: 7

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000207 AC: 25

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	CCDC78-related disorder (1)
-	-	1	Congenital myopathy with internal nuclei and atypical cores (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.16	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.092	D
MetaRNN	Benign	0.024	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.34
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.6	D
REVEL	Benign	0.17
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.52
MVP		0.34
MPC		0.39
ClinPred		0.059	T
GERP RS		2.2
Varity_R		0.38
gMVP		0.16
Mutation Taster		=58/42	polymorphism

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: rs140761899; hg19: chr16-775878;