14-57481662-T-C

Variant names:

• chr14-57481662-T-C
• rs1152522
• NM_018168.4:c.394-2A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 4P and 8B. PVS1_Strong BA1

The NM_018168.4(CCDC198):​c.394-2A>G variant causes a splice acceptor, intron 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, intron
• Scores: Splicing: ADA: 0.9999
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.100
• Publications: 26 publications found

Genes affected

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

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.11447811 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 rank	MANE	Protein	UniProt
CCDC198	NM_018168.4	c.394-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 5	ENST00000216445.8	NP_060638.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CCDC198	ENST00000216445.8	c.394-2A>G		splice_acceptor_variant, intron_variant	Intron 3 of 5	1	NM_018168.4	ENSP00000216445.3

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

GnomAD2 exomes AF: 0.744 AC: 184803 AN: 248464 AF XY: 0.756

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 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

African (AFR) AF: 0.303 AC: 9894 AN: 32688

American (AMR) AF: 0.763 AC: 33816 AN: 44308

Ashkenazi Jewish (ASJ) AF: 0.759 AC: 19663 AN: 25912

East Asian (EAS) AF: 0.955 AC: 37640 AN: 39420

South Asian (SAS) AF: 0.850 AC: 72298 AN: 85080

European-Finnish (FIN) AF: 0.712 AC: 37059 AN: 52034

Middle Eastern (MID) AF: 0.780 AC: 3742 AN: 4800

European-Non Finnish (NFE) AF: 0.736 AC: 798163 AN: 1083764

Other (OTH) AF: 0.735 AC: 43485 AN: 59192

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

African (AFR) AF: 0.314 AC: 13043 AN: 41480

American (AMR) AF: 0.738 AC: 11278 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.756 AC: 2625 AN: 3470

East Asian (EAS) AF: 0.952 AC: 4929 AN: 5180

South Asian (SAS) AF: 0.860 AC: 4149 AN: 4824

European-Finnish (FIN) AF: 0.709 AC: 7508 AN: 10584

Middle Eastern (MID) AF: 0.786 AC: 231 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50026 AN: 67990

Other (OTH) AF: 0.708 AC: 1494 AN: 2110

Alfa AF: 0.710 Hom.: 129528

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
PhyloP100		0.10
GERP RS		2.8
PromoterAI		0.0080	Neutral
Mutation Taster		=72/28	polymorphism (auto)

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

Other links and lift over

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