2-158176610-C-T

Variant summary

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

The NM_138803.4(CCDC148):c.1540G>A(p.Ala514Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,459,734 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: 6.9e-7 (0 hom.)
• Consequence: CCDC148 NM_138803.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.68

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.1540G>A	p.Ala514Thr	missense_variant	13/14	ENST00000283233.10
CCDC148-AS1	NR_038850.1	n.84C>T		non_coding_transcript_exon_variant	2/5
CCDC148	NM_001301684.2	c.1102G>A	p.Ala368Thr	missense_variant	11/12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CCDC148	ENST00000283233.10	c.1540G>A	p.Ala514Thr	missense_variant	13/14	1	NM_138803.4
CCDC148-AS1	ENST00000412781.2	n.84C>T		non_coding_transcript_exon_variant	2/5	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1459734 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 726214

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Oct 12, 2021

The c.1540G>A (p.A514T) alteration is located in exon 13 (coding exon 13) of the CCDC148 gene. This alteration results from a G to A substitution at nucleotide position 1540, causing the alanine (A) at amino acid position 514 to be replaced by a threonine (T). 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	0.38
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
Cadd	Uncertain	24
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.16	T;.
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.63	D;D
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-2.9	D;D
REVEL	Benign	0.19
Sift	Pathogenic	0.0	D;D
Sift4G	Uncertain	0.013	D;D
Polyphen		1.0	D;D
Vest4		0.81
MutPred		0.18		.;Gain of phosphorylation at A523 (P = 0.0101);
MVP		0.58
MPC		0.071
ClinPred		0.98	D
GERP RS		4.9
Varity_R		0.27
gMVP		0.48

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: rs1684600933; hg19: chr2-159033122; COSMIC: COSV51754023;