14-77114301-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_033426.3(CIPC):c.1183G>A(p.Asp395Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000686 in 1,457,844 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000069 (1 hom.)
• Consequence: CIPC NM_033426.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.675

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04490745).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CIPC	NM_033426.3	c.1183G>A	p.Asp395Asn	missense_variant	4/4	ENST00000361786.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CIPC	ENST00000361786.7	c.1183G>A	p.Asp395Asn	missense_variant	4/4	1	NM_033426.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000686 AC: 10 AN: 1457844 Hom.: 1 Cov.: 31 AF XY: 0.00000414 AC XY: 3 AN XY: 725330

Gnomad4 AFR exome AF: 0.000181

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: 0.00

Gnomad4 OTH exome AF: 0.0000665

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000577 AC: 2 AN: 3478

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

Apr 06, 2022

The c.1183G>A (p.D395N) alteration is located in exon 4 (coding exon 3) of the CIPC gene. This alteration results from a G to A substitution at nucleotide position 1183, causing the aspartic acid (D) at amino acid position 395 to be replaced by an asparagine (N). 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	0.078
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.71
Cadd	Benign	19
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0036	T
Eigen	Benign	-0.66
Eigen_PC	Benign	-0.58
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.045	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.26	N
REVEL	Benign	0.037
Sift	Uncertain	0.028	D
Sift4G	Benign	0.17	T
Polyphen		0.078	B
Vest4		0.082
MutPred		0.16		Loss of phosphorylation at S394 (P = 0.1174);
MVP		0.16
MPC		0.26
ClinPred		0.063	T
GERP RS		3.1
Varity_R		0.036
gMVP		0.45

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: rs376983062; hg19: chr14-77580644;