14-57471507-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_018168.4(CCDC198):c.739C>T(p.Leu247Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,402 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CCDC198 NM_018168.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.535

Genes affected

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

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.049540848).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC198	NM_018168.4	c.739C>T	p.Leu247Phe	missense_variant	6/6	ENST00000216445.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC198	ENST00000216445.8	c.739C>T	p.Leu247Phe	missense_variant	6/6	1	NM_018168.4	A1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251250 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135810

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461402 Hom.: 0 Cov.: 40 AF XY: 0.00000138 AC XY: 1 AN XY: 727044

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.739C>T (p.L247F) alteration is located in exon 6 (coding exon 6) of the C14orf105 gene. This alteration results from a C to T substitution at nucleotide position 739, causing the leucine (L) at amino acid position 247 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.68
Cadd	Benign	1.5
Dann	Benign	0.95
DEOGEN2	Benign	0.011	T;.;.
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.019	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.0055	T
MetaRNN	Benign	0.050	T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PROVEAN	Benign	-1.0	N;N;N
REVEL	Benign	0.036
Sift	Benign	0.34	T;T;T
Sift4G	Benign	0.29	T;T;T
Polyphen		0.0080	B;B;B
Vest4		0.032
MutPred		0.44		.;Gain of sheet (P = 0.0016);.;
MVP		0.24
MPC		0.051
ClinPred		0.021	T
GERP RS		-3.1
Varity_R		0.068
gMVP		0.032

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

Publications

LitVar

Other links and lift over

dbSNP: rs1374191015; hg19: chr14-57938225;