2-158172198-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_138803.4(CCDC148):c.1691C>A(p.Thr564Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,457,076 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: CCDC148 NM_138803.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.94

Genes affected

CCDC148 (HGNC:25191): (coiled-coil domain containing 148)

CCDC148-AS1 (HGNC:44134): (CCDC148 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CCDC148	NM_138803.4	c.1691C>A	p.Thr564Lys	missense_variant	14/14	ENST00000283233.10
CCDC148-AS1	NR_038850.1	n.75-4403G>T		intron_variant, non_coding_transcript_variant
CCDC148	NM_001301684.2	c.1253C>A	p.Thr418Lys	missense_variant	12/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC148	ENST00000283233.10	c.1691C>A	p.Thr564Lys	missense_variant	14/14	1	NM_138803.4
CCDC148-AS1	ENST00000412781.2	n.75-4403G>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000404 AC: 1 AN: 247706 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000333

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1457076 Hom.: 0 Cov.: 29 AF XY: 0.00000276 AC XY: 2 AN XY: 724768

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000234

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ExAC AF: 0.0000165 AC: 2

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

May 11, 2022

The c.1691C>A (p.T564K) alteration is located in exon 14 (coding exon 14) of the CCDC148 gene. This alteration results from a C to A substitution at nucleotide position 1691, causing the threonine (T) at amino acid position 564 to be replaced by a lysine (K). 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	Uncertain	0.37
BayesDel_addAF	Benign	-0.056	T
BayesDel_noAF	Benign	-0.14
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.18	T;.
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.83	T;T
M_CAP	Benign	0.016	T
MetaRNN	Uncertain	0.71	D;D
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.4	L;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.20
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.018	D;D
Polyphen		0.98	D;P
Vest4		0.82
MutPred		0.40		.;Gain of solvent accessibility (P = 0.012);
MVP		0.44
MPC		0.012
ClinPred		0.70	D
GERP RS		5.8
Varity_R		0.37
gMVP		0.75

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: rs143247186; hg19: chr2-159028710;