17-48075197-C-G

Variant names:

• chr17-48075197-C-G
• rs2240122
• NM_001127228.2:c.319-97G>C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001127228.2(CBX1):​c.319-97G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000203 in 491,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000020 (0 hom.)
• Consequence: CBX1 NM_001127228.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.128
• Publications: 15 publications found

Genes affected

CBX1 (HGNC:1551): (chromobox 1) This gene encodes a highly conserved nonhistone protein, which is a member of the heterochromatin protein family . The protein is enriched in the heterochromatin and associated with centromeres. The protein has a single N-terminal chromodomain which can bind to histone proteins via methylated lysine residues, and a C-terminal chromo shadow-domain (CSD) which is responsible for the homodimerization and interaction with a number of chromatin-associated nonhistone proteins. The protein may play an important role in the epigenetic control of chromatin structure and gene expression. Several related pseudogenes are located on chromosomes 1, 3, and X. Multiple alternatively spliced variants, encoding the same protein, have been identified. [provided by RefSeq, Jul 2008]

CBX1 Gene-Disease associations (from GenCC):

• neurodevelopmental disorder

  Inheritance: AD Classification: MODERATE Submitted by: G2P

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CBX1	NM_001127228.2	c.319-97G>C		intron_variant	Intron 3 of 4	ENST00000225603.9	NP_001120700.1
CBX1	NM_006807.5	c.319-97G>C		intron_variant	Intron 3 of 4		NP_006798.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CBX1	ENST00000225603.9	c.319-97G>C		intron_variant	Intron 3 of 4	1	NM_001127228.2	ENSP00000225603.4

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000203 AC: 1 AN: 491784 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 260334

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 12522

American (AMR) AF: 0.00 AC: 0 AN: 20626

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13930

East Asian (EAS) AF: 0.00 AC: 0 AN: 28720

South Asian (SAS) AF: 0.00 AC: 0 AN: 45638

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 36886

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3388

European-Non Finnish (NFE) AF: 0.00000328 AC: 1 AN: 304542

Other (OTH) AF: 0.00 AC: 0 AN: 25532

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

Alfa AF: 0.00 Hom.: 1742

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	1.8
DANN	Benign	0.84
PhyloP100		0.13

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

Other links and lift over

dbSNP: rs2240122; hg19: chr17-46152559;