NM_018168.4:c.394-2A>C

Variant names:

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

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_018168.4(CCDC198):​c.394-2A>C variant causes a splice acceptor, intron change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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: not found (cov: 33)
• 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_pathogenic. The variant received 6 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: tgtgttgtctttcatcgcAGgta. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018168.4. 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
	CCDC198	NM_018168.4	MANE Select	c.394-2A>C		splice_acceptor intron	N/A	NP_060638.2
	CCDC198	NM_001283056.2		c.394-5A>C		splice_region intron	N/A	NP_001269985.1
	CCDC198	NM_001283057.2		c.394-5A>C		splice_region intron	N/A	NP_001269986.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CCDC198	ENST00000216445.8	TSL:1 MANE Select	c.394-2A>C		splice_acceptor intron	N/A	ENSP00000216445.3
	CCDC198	ENST00000422976.6	TSL:1	c.394-5A>C		splice_region intron	N/A	ENSP00000392368.2
	CCDC198	ENST00000534126.5	TSL:1	c.394-5A>C		splice_region intron	N/A	ENSP00000434003.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 24

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.0048	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	22
DANN	Benign	0.74
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Benign	0.68	D
PhyloP100		0.10
GERP RS		2.8
PromoterAI		0.0026	Neutral
Mutation Taster		=73/27	polymorphism

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;