14-57481662-T-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_018168.4(CCDC198):c.394-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.729 in 1,579,326 control chromosomes in the GnomAD database, including 429,061 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (33245 hom., cov: 33)
  • Exomes 𝑓: 0.74 (395816 hom.)
• Consequence: CCDC198 NM_018168.4 splice_acceptor
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100

Genes affected

CCDC198 (HGNC:20189): (coiled-coil domain containing 198)

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.11335578 fraction of the gene. Cryptic splice site detected, with MaxEntScore 11, offset of 3, new splice context is: tgtgttgtctttcatggcAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.929 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC198	NM_018168.4	c.394-2A>G		splice_acceptor_variant		ENST00000216445.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC198	ENST00000216445.8	c.394-2A>G		splice_acceptor_variant		1	NM_018168.4	A1

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95728 AN: 152010 Hom.: 33243 Cov.: 33

Gnomad AFR AF: 0.315

Gnomad AMI AF: 0.512

Gnomad AMR AF: 0.737

Gnomad ASJ AF: 0.756

Gnomad EAS AF: 0.951

Gnomad SAS AF: 0.860

Gnomad FIN AF: 0.709

Gnomad MID AF: 0.797

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.708

GnomAD3 exomes AF: 0.744 AC: 184803 AN: 248464 Hom.: 71028 AF XY: 0.756 AC XY: 101516 AN XY: 134328

Gnomad AFR exome AF: 0.307

Gnomad AMR exome AF: 0.768

Gnomad ASJ exome AF: 0.761

Gnomad EAS exome AF: 0.956

Gnomad SAS exome AF: 0.855

Gnomad FIN exome AF: 0.713

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.757

GnomAD4 exome AF: 0.740 AC: 1055760 AN: 1427198 Hom.: 395816 Cov.: 24 AF XY: 0.744 AC XY: 530031 AN XY: 711990

Gnomad4 AFR exome AF: 0.303

Gnomad4 AMR exome AF: 0.763

Gnomad4 ASJ exome AF: 0.759

Gnomad4 EAS exome AF: 0.955

Gnomad4 SAS exome AF: 0.850

Gnomad4 FIN exome AF: 0.712

Gnomad4 NFE exome AF: 0.736

Gnomad4 OTH exome AF: 0.735

GnomAD4 genome AF: 0.629 AC: 95748 AN: 152128 Hom.: 33245 Cov.: 33 AF XY: 0.638 AC XY: 47411 AN XY: 74346

Gnomad4 AFR AF: 0.314

Gnomad4 AMR AF: 0.738

Gnomad4 ASJ AF: 0.756

Gnomad4 EAS AF: 0.952

Gnomad4 SAS AF: 0.860

Gnomad4 FIN AF: 0.709

Gnomad4 NFE AF: 0.736

Gnomad4 OTH AF: 0.708

Alfa AF: 0.721 Hom.: 64456

Bravo AF: 0.616

TwinsUK AF: 0.731 AC: 2709

ALSPAC AF: 0.724 AC: 2791

ESP6500AA AF: 0.312 AC: 1376

ESP6500EA AF: 0.745 AC: 6405

ExAC AF: 0.736 AC: 89348

Asia WGS AF: 0.839 AC: 2917 AN: 3478

EpiCase AF: 0.748

EpiControl AF: 0.757

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.27
Cadd	Benign	22
Dann	Benign	0.74
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.47	N
MutationTaster	Benign	6.9e-8	P;P;P
GERP RS		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.74
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.97		Position offset: -2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1152522; hg19: chr14-57948380; COSMIC: COSV53603802; COSMIC: COSV53603802;