Genetic Variant CCDC78:p.Gly368Glu (chr16-723887-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001378030.1(CCDC78):c.1103G>A(p.Gly368Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000613 in 1,598,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G368R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00016 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000050 ( 0 hom. )

Consequence

CCDC78
NM_001378030.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.863

Publications

3 publications found

Variant links:

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

CCDC78 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0063400567).

BS2

High AC in GnomAd4 at 25 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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC78	NM_001378030.1	MANE Select	c.1103G>A	p.Gly368Glu	missense	Exon 11 of 14	NP_001364959.1	H3BLT8
CCDC78	NM_001031737.3		c.1103G>A	p.Gly368Glu	missense	Exon 11 of 14	NP_001026907.2	A2IDD5-1
CCDC78	NM_001378033.1		c.536G>A	p.Gly179Glu	missense	Exon 7 of 10	NP_001364962.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CCDC78	ENST00000345165.10	TSL:5 MANE Select	c.1103G>A	p.Gly368Glu	missense	Exon 11 of 14	ENSP00000316851.5	H3BLT8
CCDC78	ENST00000293889.10	TSL:1	c.1103G>A	p.Gly368Glu	missense	Exon 11 of 14	ENSP00000293889.6	A2IDD5-1
CCDC78	ENST00000947033.1		c.1103G>A	p.Gly368Glu	missense	Exon 11 of 14	ENSP00000617092.1

Frequencies

GnomAD3 genomes

AF:

0.000164

AC:

AN:

152246

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

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:

0.0000735

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000107

AC:

AN:

223350

AF XY:

0.0000743

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000589

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000304

Gnomad OTH exome

AF:

0.000363

GnomAD4 exome

AF:

0.0000505

AC:

AN:

1446378

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

718122

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33176

American (AMR)

AF:

0.000607

AC:

AN:

42860

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25816

East Asian (EAS)

AF:

0.00

AC:

AN:

39058

South Asian (SAS)

AF:

0.00

AC:

AN:

83934

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51182

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5738

European-Non Finnish (NFE)

AF:

0.0000389

AC:

AN:

1104882

Other (OTH)

AF:

0.0000670

AC:

AN:

59732

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.455

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000164

AC:

AN:

152364

Hom.:

Cov.:

AF XY:

0.000215

AC XY:

AN XY:

74510

show subpopulations

African (AFR)

AF:

0.0000240

AC:

AN:

41584

American (AMR)

AF:

0.00118

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10626

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000735

AC:

AN:

68036

Other (OTH)

AF:

0.000473

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.515

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000219

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000416

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital myopathy with internal nuclei and atypical cores (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.71

CADD

Benign

0.090

(source)

DANN

Benign

0.50

DEOGEN2

Benign

0.0014

Eigen

Benign

-1.7

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0038

LIST_S2

Benign

0.46

M_CAP

Benign

0.0038

MetaRNN

Benign

0.0063

MetaSVM

Benign

-0.97

MutationAssessor

Benign

-1.1

PhyloP100

-0.86

PrimateAI

Benign

0.31

PROVEAN

Benign

1.5

REVEL

Benign

0.028

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0010

Vest4

0.065

MVP

0.030

MPC

0.078

ClinPred

0.052

GERP RS

-1.8

Varity_R

0.034

gMVP

0.029

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over