4-76351790-C-T

Position:

• chr4-76351790-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001394954.1(CCDC158):​c.2468G>A​(p.Cys823Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CCDC158 NM_001394954.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.79

Genes affected

CCDC158 (HGNC:26374): (coiled-coil domain containing 158)

CCDC158 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.766

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CCDC158	NM_001394954.1	c.2468G>A	p.Cys823Tyr	missense_variant	17/25	ENST00000682701.1	NP_001381883.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CCDC158	ENST00000682701.1	c.2468G>A	p.Cys823Tyr	missense_variant	17/25		NM_001394954.1	ENSP00000507278.1
CCDC158	ENST00000504667.2	n.2289G>A		non_coding_transcript_exon_variant	5/13	1
CCDC158	ENST00000388914.7	c.2468G>A	p.Cys823Tyr	missense_variant	16/24	5		ENSP00000373566.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

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

Feb 28, 2024

The c.2468G>A (p.C823Y) alteration is located in exon 16 (coding exon 15) of the CCDC158 gene. This alteration results from a G to A substitution at nucleotide position 2468, causing the cysteine (C) at amino acid position 823 to be replaced by a tyrosine (Y). 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	Pathogenic	0.79
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0090	T
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.010	T
MetaRNN	Pathogenic	0.77	D
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.90	L
MutationTaster	Benign	0.98	D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-2.2	N
REVEL	Uncertain	0.30
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.090	T
Polyphen		1.0	D
Vest4		0.91
MutPred		0.29		Loss of disorder (P = 0.0983);
MVP		0.76
MPC		0.25
ClinPred		0.96	D
GERP RS		5.9
Varity_R		0.64
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs909965143; hg19: chr4-77272943;