chr14-77105832-T-A

Position:

• chr14-77105832-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_033426.3(CIPC):​c.124T>A​(p.Ser42Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CIPC NM_033426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.22

Genes affected

CIPC (HGNC:20365): (CLOCK interacting pacemaker) Predicted to be involved in negative regulation of circadian rhythm and negative regulation of transcription, DNA-templated. Located in cytosol; nucleolus; and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000259164 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.29672575).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CIPC	NM_033426.3	c.124T>A	p.Ser42Thr	missense_variant	2/4	ENST00000361786.7	NP_219494.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CIPC	ENST00000361786.7	c.124T>A	p.Ser42Thr	missense_variant	2/4	1	NM_033426.3	ENSP00000355319.2
ENSG00000259164	ENST00000557752.1	n.124T>A		non_coding_transcript_exon_variant	2/6	5		ENSP00000456507.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000402 AC: 1 AN: 248486 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 134296

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: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000887

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jan 16, 2024

The c.124T>A (p.S42T) alteration is located in exon 2 (coding exon 1) of the CIPC gene. This alteration results from a T to A substitution at nucleotide position 124, causing the serine (S) at amino acid position 42 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	Pathogenic	0.58
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.084	T;.;.;.;.;.;.
Eigen	Uncertain	0.38
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.84	T;T;T;T;T;T;T
M_CAP	Benign	0.073	D
MetaRNN	Benign	0.30	T;T;T;T;T;T;T
MetaSVM	Benign	-0.39	T
MutationAssessor	Uncertain	2.8	M;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-2.0	N;D;D;D;D;D;D
REVEL	Benign	0.17
Sift	Uncertain	0.010	D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Polyphen		0.61	P;.;.;.;.;.;.
Vest4		0.81
MVP		0.75
MPC		0.77
ClinPred		0.93	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.31

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: rs1238033986; hg19: chr14-77572175;