rs142136104

Positions:

• chr16-724734-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001378030.1(CCDC78):​c.712A>C​(p.Lys238Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0111 in 1,612,256 control chromosomes in the GnomAD database, including 120 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (9 hom., cov: 34)
  • Exomes 𝑓: 0.011 (111 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.0300

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00590384).
• BP6: Variant 16-724734-T-G is Benign according to our data. Variant chr16-724734-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 128630.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-724734-T-G is described in Lovd as [Likely_benign]. Variant chr16-724734-T-G is described in Lovd as [Benign].
• BS2: High AC in GnomAd4 at 1242 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC78	NM_001378030.1	c.712A>C	p.Lys238Gln	missense_variant	8/14	ENST00000345165.10	NP_001364959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC78	ENST00000345165.10	c.712A>C	p.Lys238Gln	missense_variant	8/14	5	NM_001378030.1	ENSP00000316851	A2

Frequencies

GnomAD3 genomes AF: 0.00816 AC: 1242 AN: 152190 Hom.: 9 Cov.: 34

Gnomad AFR AF: 0.00220

Gnomad AMI AF: 0.0385

Gnomad AMR AF: 0.00249

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00434

Gnomad FIN AF: 0.0203

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0121

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.00912 AC: 2257 AN: 247470 Hom.: 13 AF XY: 0.00926 AC XY: 1247 AN XY: 134700

Gnomad AFR exome AF: 0.00202

Gnomad AMR exome AF: 0.00239

Gnomad ASJ exome AF: 0.00503

Gnomad EAS exome AF: 0.0000549

Gnomad SAS exome AF: 0.00638

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.0130

Gnomad OTH exome AF: 0.00845

GnomAD4 exome AF: 0.0114 AC: 16699 AN: 1459948 Hom.: 111 Cov.: 38 AF XY: 0.0113 AC XY: 8208 AN XY: 726232

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.00536

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00636

Gnomad4 FIN exome AF: 0.0185

Gnomad4 NFE exome AF: 0.0128

Gnomad4 OTH exome AF: 0.00918

GnomAD4 genome AF: 0.00815 AC: 1242 AN: 152308 Hom.: 9 Cov.: 34 AF XY: 0.00833 AC XY: 620 AN XY: 74468

Gnomad4 AFR AF: 0.00219

Gnomad4 AMR AF: 0.00248

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0203

Gnomad4 NFE AF: 0.0121

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.0100 Hom.: 5

Bravo AF: 0.00679

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00206 AC: 9

ESP6500EA AF: 0.0124 AC: 106

ExAC AF: 0.00941 AC: 1134

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0108

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 19, 2023	See Variant Classification Assertion Criteria. -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2024	CCDC78: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Sep 02, 2016	- -

Congenital myopathy with internal nuclei and atypical cores Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.50	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.37
Eigen_PC	Benign	-0.45
FATHMM_MKL	Benign	0.34	N
LIST_S2	Benign	0.56	T
MetaRNN	Benign	0.0059	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.5	M
MutationTaster	Benign	1.0	N;D;D
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.037
Sift	Benign	0.089	T
Sift4G	Uncertain	0.017	D
Polyphen		0.93	P
Vest4		0.27
MVP		0.13
MPC		0.23
ClinPred		0.011	T
GERP RS		3.1
Varity_R		0.075
gMVP		0.049

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs142136104; hg19: chr16-774734;