rs760280521

chr16-722948-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The ENST00000293889.10(CCDC78):c.1271G>A(p.Arg424Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000391 in 1,612,390 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. R424R) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: CCDC78 ENST00000293889.10 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.202

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018242717).
• BP6: Variant 16-722948-C-T is Benign according to our data. Variant chr16-722948-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 473252.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High AC in GnomAd at 20 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC78	NM_001378030.1	c.1275G>A	p.Gln425=	synonymous_variant	13/14	ENST00000345165.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC78	ENST00000345165.10	c.1275G>A	p.Gln425=	synonymous_variant	13/14	5	NM_001378030.1	A2

Frequencies

GnomAD3 genomes AF: 0.000131 AC: 20 AN: 152228 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000128 AC: 32 AN: 249544 Hom.: 0 AF XY: 0.000111 AC XY: 15 AN XY: 135490

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000897

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.0000301 AC: 44 AN: 1460044 Hom.: 0 Cov.: 34 AF XY: 0.0000275 AC XY: 20 AN XY: 726324

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152346 Hom.: 0 Cov.: 34 AF XY: 0.000174 AC XY: 13 AN XY: 74502

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00124

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.000227

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ExAC AF: 0.0000578 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 07, 2024

The c.1271G>A (p.R424K) alteration is located in exon 13 (coding exon 13) of the CCDC78 gene. This alteration results from a G to A substitution at nucleotide position 1271, causing the arginine (R) at amino acid position 424 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Congenital myopathy with internal nuclei and atypical cores Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 28, 2023

- -

CCDC78-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 08, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.51
Cadd	Benign	9.1
Dann	Benign	0.97
DEOGEN2	Benign	0.0043	T
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.42
FATHMM_MKL	Uncertain	0.76	D
LIST_S2	Benign	0.35	T
M_CAP	Benign	0.026	D
MetaRNN	Benign	0.018	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.63	N
MutationTaster	Benign	1.0	N;D;D
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-0.75	N
REVEL	Benign	0.037
Sift	Benign	0.24	T
Sift4G	Pathogenic	0.0	D
Polyphen		0.041	B
Vest4		0.34
MutPred		0.31		Gain of methylation at R424 (P = 0.0396);
MVP		0.16
MPC		0.37
ClinPred		0.082	T
GERP RS		-0.83
Varity_R		0.078
gMVP		0.27

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs760280521; hg19: chr16-772948; COSMIC: COSV53497742; COSMIC: COSV53497742;