16-724116-C-T

Variant names:

• chr16-724116-C-T
• rs142170929
• NM_001378030.1:c.1043G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001378030.1(CCDC78):​c.1043G>A​(p.Arg348Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000267 in 1,594,716 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R348W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0015 (2 hom., cov: 33)
  • Exomes 𝑓: 0.00014 (2 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -4.43
• Publications: 1 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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031380951).
• BP6: Variant 16-724116-C-T is Benign according to our data. Variant chr16-724116-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 540481.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 223 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.1043G>A	p.Arg348Gln	missense	Exon 10 of 14	NP_001364959.1	H3BLT8
	CCDC78	NM_001031737.3		c.1043G>A	p.Arg348Gln	missense	Exon 10 of 14	NP_001026907.2	A2IDD5-1
	CCDC78	NM_001378033.1		c.476G>A	p.Arg159Gln	missense	Exon 6 of 10	NP_001364962.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	ENST00000345165.10	TSL:5 MANE Select	c.1043G>A	p.Arg348Gln	missense	Exon 10 of 14	ENSP00000316851.5	H3BLT8
	CCDC78	ENST00000293889.10	TSL:1	c.1043G>A	p.Arg348Gln	missense	Exon 10 of 14	ENSP00000293889.6	A2IDD5-1
	CCDC78	ENST00000947033.1		c.1043G>A	p.Arg348Gln	missense	Exon 10 of 14	ENSP00000617092.1

Frequencies

GnomAD3 genomes AF: 0.00147 AC: 223 AN: 152138 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00517

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

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: 0.000956

GnomAD2 exomes AF: 0.000443 AC: 104 AN: 234572 AF XY: 0.000394

Gnomad AFR exome AF: 0.00528

Gnomad AMR exome AF: 0.000463

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000944

Gnomad OTH exome AF: 0.000352

GnomAD4 exome AF: 0.000140 AC: 202 AN: 1442460 Hom.: 2 Cov.: 34 AF XY: 0.000126 AC XY: 90 AN XY: 716038

African (AFR) AF: 0.00465 AC: 153 AN: 32888

American (AMR) AF: 0.000400 AC: 17 AN: 42504

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24826

East Asian (EAS) AF: 0.00 AC: 0 AN: 39516

South Asian (SAS) AF: 0.0000838 AC: 7 AN: 83500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51464

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5632

European-Non Finnish (NFE) AF: 0.00000544 AC: 6 AN: 1102626

Other (OTH) AF: 0.000319 AC: 19 AN: 59504

GnomAD4 genome AF: 0.00146 AC: 223 AN: 152256 Hom.: 2 Cov.: 33 AF XY: 0.00154 AC XY: 115 AN XY: 74446

African (AFR) AF: 0.00515 AC: 214 AN: 41540

American (AMR) AF: 0.000392 AC: 6 AN: 15304

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000801 Hom.: 0

Bravo AF: 0.00149

ESP6500AA AF: 0.00545 AC: 24

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000544 AC: 66

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	CCDC78-related disorder (1)
-	-	1	Congenital myopathy with internal nuclei and atypical cores (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	0.020
DANN	Benign	0.72
DEOGEN2	Benign	0.0070	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.48	T
M_CAP	Benign	0.0010	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.1	N
PhyloP100		-4.4
PrimateAI	Benign	0.20	T
PROVEAN	Benign	-0.32	N
REVEL	Benign	0.031
Sift	Benign	0.45	T
Sift4G	Benign	0.42	T
Polyphen		0.017	B
Vest4		0.089
MVP		0.048
MPC		0.071
ClinPred		0.011	T
GERP RS		-8.0
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.8
Varity_R		0.017
gMVP		0.063
Mutation Taster		=91/9	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: rs142170929; hg19: chr16-774116; COSMIC: COSV53497514; COSMIC: COSV53497514;