2-158220601-C-G

Position:

• chr2-158220601-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000283233.10(CCDC148):​c.1364G>C​(p.Arg455Thr) variant causes a missense 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: CCDC148 ENST00000283233.10 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.651

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.21023968).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC148	NM_138803.4	c.1364G>C	p.Arg455Thr	missense_variant	11/14	ENST00000283233.10	NP_620158.3
CCDC148-AS1	NR_038850.1	n.355+12984C>G		intron_variant, non_coding_transcript_variant
CCDC148	NM_001301684.2	c.926G>C	p.Arg309Thr	missense_variant	9/12		NP_001288613.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC148	ENST00000283233.10	c.1364G>C	p.Arg455Thr	missense_variant	11/14	1	NM_138803.4	ENSP00000283233
CCDC148-AS1	ENST00000412781.2	n.355+12984C>G		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

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

Dec 22, 2023

The c.1364G>C (p.R455T) alteration is located in exon 11 (coding exon 11) of the CCDC148 gene. This alteration results from a G to C substitution at nucleotide position 1364, causing the arginine (R) at amino acid position 455 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	Benign	0.17
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.47
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0096	T;.
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.095
FATHMM_MKL	Benign	0.72	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Benign	0.0097	T
MetaRNN	Benign	0.21	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.5	M;.
MutationTaster	Benign	0.58	D;D
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N;N
REVEL	Benign	0.016
Sift	Uncertain	0.0090	D;D
Sift4G	Uncertain	0.031	D;D
Polyphen		0.40	B;B
Vest4		0.65
MutPred		0.17		.;Gain of loop (P = 0.0166);
MVP		0.38
MPC		0.054
ClinPred		0.70	D
GERP RS		2.1
Varity_R		0.15
gMVP		0.16

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: rs1687124052; hg19: chr2-159077113;