rs12448311

Variant names:

• chr16-725954-C-A
• rs12448311
• NM_001378030.1:c.180+12G>T

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.180+12G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.235 in 1,560,678 control chromosomes in the GnomAD database, including 46,014 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3373 hom., cov: 33)
  • Exomes 𝑓: 0.24 (42641 hom.)
• Consequence: CCDC78 NM_001378030.1 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -1.34
• Publications: 3 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=-0.83).
• BP6: Variant 16-725954-C-A is Benign according to our data. Variant chr16-725954-C-A is described in ClinVar as Benign. ClinVar VariationId is 257164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.304 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CCDC78	NM_001378030.1	c.180+12G>T		intron_variant	Intron 2 of 13	ENST00000345165.10	NP_001364959.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC78	ENST00000345165.10	c.180+12G>T		intron_variant	Intron 2 of 13	5	NM_001378030.1	ENSP00000316851.5

Frequencies

GnomAD3 genomes AF: 0.198 AC: 30060 AN: 151908 Hom.: 3367 Cov.: 33

Gnomad AFR AF: 0.126

Gnomad AMI AF: 0.273

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.183

Gnomad EAS AF: 0.0127

Gnomad SAS AF: 0.315

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.184

GnomAD2 exomes AF: 0.210 AC: 35590 AN: 169314 AF XY: 0.222

Gnomad AFR exome AF: 0.127

Gnomad AMR exome AF: 0.108

Gnomad ASJ exome AF: 0.174

Gnomad EAS exome AF: 0.00819

Gnomad FIN exome AF: 0.265

Gnomad NFE exome AF: 0.251

Gnomad OTH exome AF: 0.210

GnomAD4 exome AF: 0.239 AC: 336507 AN: 1408652 Hom.: 42641 Cov.: 38 AF XY: 0.242 AC XY: 168460 AN XY: 696156

African (AFR) AF: 0.122 AC: 3907 AN: 32124

American (AMR) AF: 0.111 AC: 4125 AN: 37138

Ashkenazi Jewish (ASJ) AF: 0.179 AC: 4538 AN: 25348

East Asian (EAS) AF: 0.0222 AC: 817 AN: 36864

South Asian (SAS) AF: 0.320 AC: 25885 AN: 81014

European-Finnish (FIN) AF: 0.265 AC: 12742 AN: 48128

Middle Eastern (MID) AF: 0.154 AC: 880 AN: 5706

European-Non Finnish (NFE) AF: 0.250 AC: 271009 AN: 1083976

Other (OTH) AF: 0.216 AC: 12604 AN: 58354

GnomAD4 genome AF: 0.198 AC: 30091 AN: 152026 Hom.: 3373 Cov.: 33 AF XY: 0.199 AC XY: 14799 AN XY: 74322

African (AFR) AF: 0.127 AC: 5254 AN: 41528

American (AMR) AF: 0.153 AC: 2337 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.183 AC: 635 AN: 3468

East Asian (EAS) AF: 0.0129 AC: 67 AN: 5182

South Asian (SAS) AF: 0.317 AC: 1527 AN: 4814

European-Finnish (FIN) AF: 0.258 AC: 2734 AN: 10588

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.248 AC: 16849 AN: 67854

Other (OTH) AF: 0.184 AC: 387 AN: 2108

Alfa AF: 0.231 Hom.: 808

Bravo AF: 0.181

Asia WGS AF: 0.191 AC: 663 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jul 15, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Congenital myopathy with internal nuclei and atypical cores Benign:1

Dec 06, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.45
DANN	Benign	0.56
PhyloP100		-1.3
PromoterAI		-0.013	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs12448311; hg19: chr16-775954; COSMIC: COSV52402262; COSMIC: COSV52402262;