15-90233877-GC-GCC

Variant names:

• chr15-90233877-G-GC
• rs1296353492
• NM_006384.4:c.8dupG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_006384.4(CIB1):​c.8dupG​(p.Ser4LeufsTer33) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000378 in 1,321,602 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G3G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000038 (0 hom.)
• Consequence: CIB1 NM_006384.4 frameshift
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.12
• Publications: 0 publications found

Genes affected

CIB1 (HGNC:16920): (calcium and integrin binding 1) This gene encodes a member of the EF-hand domain-containing calcium-binding superfamily. The encoded protein interacts with many other proteins, including the platelet integrin alpha-IIb-beta-3, DNA-dependent protein kinase, presenilin-2, focal adhesion kinase, p21 activated kinase, and protein kinase D. The encoded protein may be involved in cell survival and proliferation, and is associated with several disease states including cancer and Alzheimer's disease. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Apr 2013]

GDPGP1 (HGNC:34360): (GDP-D-glucose phosphorylase 1) Enables GDP-D-glucose phosphorylase activity. Involved in glucose metabolic process. Predicted to be active in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 8 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006384.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIB1	NM_006384.4	MANE Select	c.8dupG	p.Ser4LeufsTer33	frameshift	Exon 1 of 7	NP_006375.2	Q99828-1
	CIB1	NM_001277764.2		c.8dupG	p.Ser4LeufsTer38	frameshift	Exon 1 of 7	NP_001264693.1	Q99828-2
	CIB1	NR_102427.1		n.237+41dupG		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CIB1	ENST00000328649.11	TSL:1 MANE Select	c.8dupG	p.Ser4LeufsTer33	frameshift	Exon 1 of 7	ENSP00000333873.6	Q99828-1
	CIB1	ENST00000612800.1	TSL:1	c.8dupG	p.Ser4LeufsTer38	frameshift	Exon 1 of 7	ENSP00000479860.1	Q99828-2
	CIB1	ENST00000970526.1		c.8dupG	p.Ser4LeufsTer33	frameshift	Exon 1 of 7	ENSP00000640585.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000378 AC: 5 AN: 1321602 Hom.: 0 Cov.: 32 AF XY: 0.00000619 AC XY: 4 AN XY: 646138

African (AFR) AF: 0.00 AC: 0 AN: 28692

American (AMR) AF: 0.00 AC: 0 AN: 24318

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19956

East Asian (EAS) AF: 0.00 AC: 0 AN: 34714

South Asian (SAS) AF: 0.00 AC: 0 AN: 67828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39966

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3754

European-Non Finnish (NFE) AF: 0.00000477 AC: 5 AN: 1047778

Other (OTH) AF: 0.00 AC: 0 AN: 54596

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1296353492; hg19: chr15-90777109;