rs148595483

Variant names:

• chr16-724193-G-T
• rs148595483
• NM_001378030.1:c.966C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-724193-G-T
• chr16-724193-G-A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001378030.1(CCDC78):​c.966C>A​(p.Asn322Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00392 in 1,597,364 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0025 (1 hom., cov: 33)
  • Exomes 𝑓: 0.0041 (42 hom.)
• Consequence: CCDC78 NM_001378030.1 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.909
• Publications: 5 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: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• centronuclear myopathy

  Inheritance: AD Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003260076).
• BP6: Variant 16-724193-G-T is Benign according to our data. Variant chr16-724193-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 128634.
• BS2: High AC in GnomAd4 at 385 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	NM_001378030.1	MANE Select	c.966C>A	p.Asn322Lys	missense	Exon 10 of 14	NP_001364959.1	H3BLT8
	CCDC78	NM_001031737.3		c.966C>A	p.Asn322Lys	missense	Exon 10 of 14	NP_001026907.2	A2IDD5-1
	CCDC78	NM_001378033.1		c.399C>A	p.Asn133Lys	missense	Exon 6 of 10	NP_001364962.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC78	ENST00000345165.10	TSL:5 MANE Select	c.966C>A	p.Asn322Lys	missense	Exon 10 of 14	ENSP00000316851.5	H3BLT8
	CCDC78	ENST00000293889.10	TSL:1	c.966C>A	p.Asn322Lys	missense	Exon 10 of 14	ENSP00000293889.6	A2IDD5-1
	CCDC78	ENST00000947033.1		c.966C>A	p.Asn322Lys	missense	Exon 10 of 14	ENSP00000617092.1

Frequencies

GnomAD3 genomes AF: 0.00253 AC: 385 AN: 152208 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000893

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.0157

Gnomad FIN AF: 0.000282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00362

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00376 AC: 885 AN: 235528 AF XY: 0.00456

Gnomad AFR exome AF: 0.000878

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.000233

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000481

Gnomad NFE exome AF: 0.00321

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00407 AC: 5880 AN: 1445038 Hom.: 42 Cov.: 35 AF XY: 0.00440 AC XY: 3156 AN XY: 717322

African (AFR) AF: 0.000574 AC: 19 AN: 33120

American (AMR) AF: 0.000628 AC: 27 AN: 43022

Ashkenazi Jewish (ASJ) AF: 0.0000800 AC: 2 AN: 24988

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39526

South Asian (SAS) AF: 0.0156 AC: 1312 AN: 83854

European-Finnish (FIN) AF: 0.000562 AC: 29 AN: 51632

Middle Eastern (MID) AF: 0.00176 AC: 10 AN: 5698

European-Non Finnish (NFE) AF: 0.00391 AC: 4318 AN: 1103530

Other (OTH) AF: 0.00272 AC: 162 AN: 59668

GnomAD4 genome AF: 0.00253 AC: 385 AN: 152326 Hom.: 1 Cov.: 33 AF XY: 0.00260 AC XY: 194 AN XY: 74484

African (AFR) AF: 0.000890 AC: 37 AN: 41572

American (AMR) AF: 0.00105 AC: 16 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.0157 AC: 76 AN: 4828

European-Finnish (FIN) AF: 0.000282 AC: 3 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00362 AC: 246 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2114

Alfa AF: 0.00339 Hom.: 2

Bravo AF: 0.00206

TwinsUK AF: 0.00351 AC: 13

ALSPAC AF: 0.00415 AC: 16

ESP6500AA AF: 0.000910 AC: 4

ESP6500EA AF: 0.00279 AC: 24

ExAC AF: 0.00371 AC: 450

Asia WGS AF: 0.00664 AC: 23 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.71
CADD	Benign	7.3
DANN	Benign	0.55
DEOGEN2	Benign	0.015	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.37	T
MetaRNN	Benign	0.0033	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		0.91
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.63	N
REVEL	Benign	0.021
Sift	Benign	0.47	T
Sift4G	Uncertain	0.037	D
Polyphen		0.027	B
Vest4		0.060
MutPred		0.35		Gain of methylation at N322 (P = 0.009)
MVP		0.11
MPC		0.21
ClinPred		0.00010	T
GERP RS		1.8
Varity_R		0.047
gMVP		0.11
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs148595483; hg19: chr16-774193; COSMIC: COSV107269014; COSMIC: COSV107269014;