16-724520-C-T

Variant names:

• chr16-724520-C-T
• rs4984921
• NM_001378030.1:c.766-11G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001378030.1(CCDC78):​c.766-11G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.494 in 1,589,550 control chromosomes in the GnomAD database, including 203,337 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18866 hom., cov: 33)
  • Exomes 𝑓: 0.50 (184471 hom.)
• Consequence: CCDC78 NM_001378030.1 intron
• Scores: Splicing: ADA: 0.0005553
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -3.61
• Publications: 14 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae)
• centronuclear myopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 16-724520-C-T is Benign according to our data. Variant chr16-724520-C-T is described in ClinVar as Benign. ClinVar VariationId is 257169.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.787 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	NM_001378030.1	MANE Select	c.766-11G>A		intron	N/A	NP_001364959.1
	CCDC78	NR_165382.1		n.1312G>A		non_coding_transcript_exon	Exon 6 of 10
	CCDC78	NR_165383.1		n.958G>A		non_coding_transcript_exon	Exon 8 of 13

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	ENST00000345165.10	TSL:5 MANE Select	c.766-11G>A		intron	N/A	ENSP00000316851.5
	CCDC78	ENST00000293889.10	TSL:1	c.766-11G>A		intron	N/A	ENSP00000293889.6
	CCDC78	ENST00000463539.5	TSL:2	n.1077G>A		non_coding_transcript_exon	Exon 7 of 12

Frequencies

GnomAD3 genomes AF: 0.485 AC: 73694 AN: 151906 Hom.: 18839 Cov.: 33

Gnomad AFR AF: 0.393

Gnomad AMI AF: 0.456

Gnomad AMR AF: 0.579

Gnomad ASJ AF: 0.396

Gnomad EAS AF: 0.808

Gnomad SAS AF: 0.762

Gnomad FIN AF: 0.603

Gnomad MID AF: 0.424

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.451

GnomAD2 exomes AF: 0.574 AC: 120458 AN: 209688 AF XY: 0.573

Gnomad AFR exome AF: 0.399

Gnomad AMR exome AF: 0.715

Gnomad ASJ exome AF: 0.397

Gnomad EAS exome AF: 0.816

Gnomad FIN exome AF: 0.612

Gnomad NFE exome AF: 0.465

Gnomad OTH exome AF: 0.495

GnomAD4 exome AF: 0.495 AC: 712055 AN: 1437526 Hom.: 184471 Cov.: 54 AF XY: 0.502 AC XY: 358898 AN XY: 714906

African (AFR) AF: 0.382 AC: 12684 AN: 33178

American (AMR) AF: 0.695 AC: 30248 AN: 43504

Ashkenazi Jewish (ASJ) AF: 0.397 AC: 10286 AN: 25938

East Asian (EAS) AF: 0.799 AC: 31277 AN: 39160

South Asian (SAS) AF: 0.753 AC: 64328 AN: 85428

European-Finnish (FIN) AF: 0.607 AC: 22903 AN: 37724

Middle Eastern (MID) AF: 0.365 AC: 2100 AN: 5750

European-Non Finnish (NFE) AF: 0.460 AC: 508880 AN: 1107040

Other (OTH) AF: 0.491 AC: 29349 AN: 59804

GnomAD4 genome AF: 0.485 AC: 73760 AN: 152024 Hom.: 18866 Cov.: 33 AF XY: 0.501 AC XY: 37198 AN XY: 74312

African (AFR) AF: 0.393 AC: 16292 AN: 41452

American (AMR) AF: 0.580 AC: 8862 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.396 AC: 1374 AN: 3472

East Asian (EAS) AF: 0.808 AC: 4154 AN: 5144

South Asian (SAS) AF: 0.763 AC: 3683 AN: 4828

European-Finnish (FIN) AF: 0.603 AC: 6385 AN: 10584

Middle Eastern (MID) AF: 0.422 AC: 124 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31507 AN: 67940

Other (OTH) AF: 0.456 AC: 964 AN: 2114

Alfa AF: 0.478 Hom.: 3306

Bravo AF: 0.472

Asia WGS AF: 0.741 AC: 2572 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Congenital myopathy with internal nuclei and atypical cores (2)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.0
DANN	Benign	0.72
PhyloP100		-3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00056
dbscSNV1_RF	Benign	0.038
SpliceAI score (max)		0.080		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: rs4984921; hg19: chr16-774520;