rs3751954

Variant names:

• chr17-79779686-A-G
• rs3751954
• NM_005189.3:c.182+259A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005189.3(CBX2):​c.182+259A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.109 in 531,454 control chromosomes in the GnomAD database, including 3,687 homozygotes. 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: 𝑓 0.10 (994 hom., cov: 34)
  • Exomes 𝑓: 0.11 (2693 hom.)
• Consequence: CBX2 NM_005189.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.198
• Publications: 2 publications found

Genes affected

CBX2 (HGNC:1552): (chromobox 2) This gene encodes a component of the polycomb multiprotein complex, which is required to maintain the transcriptionally repressive state of many genes throughout development via chromatin remodeling and modification of histones. Disruption of this gene in mice results in male-to-female gonadal sex reversal. Mutations in this gene are also associated with gonadal dysgenesis in humans. Alternatively spliced transcript variants encoding different isoforms have been noted for this gene.[provided by RefSeq, Mar 2010]

CBX2 Gene-Disease associations (from GenCC):

• 46,XY complete gonadal dysgenesis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 46,XY sex reversal 5

  Inheritance: AR, SD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005189.3. 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
	CBX2	NM_005189.3	MANE Select	c.182+259A>G		intron	N/A	NP_005180.1	Q14781-1
	CBX2	NM_032647.4		c.182+259A>G		intron	N/A	NP_116036.1	Q14781-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CBX2	ENST00000310942.9	TSL:1 MANE Select	c.182+259A>G		intron	N/A	ENSP00000308750.4	Q14781-1
	CBX2	ENST00000269399.5	TSL:1	c.182+259A>G		intron	N/A	ENSP00000269399.5	Q14781-2
	CBX2	ENST00000571484.1	TSL:1	n.514A>G		non_coding_transcript_exon	Exon 3 of 3

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15354 AN: 152180 Hom.: 987 Cov.: 34

Gnomad AFR AF: 0.0486

Gnomad AMI AF: 0.0824

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.0700

Gnomad EAS AF: 0.102

Gnomad SAS AF: 0.0959

Gnomad FIN AF: 0.163

Gnomad MID AF: 0.0318

Gnomad NFE AF: 0.107

Gnomad OTH AF: 0.102

GnomAD4 exome AF: 0.112 AC: 42554 AN: 379156 Hom.: 2693 Cov.: 0 AF XY: 0.111 AC XY: 22024 AN XY: 198336

African (AFR) AF: 0.0480 AC: 536 AN: 11172

American (AMR) AF: 0.236 AC: 4001 AN: 16950

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 867 AN: 11812

East Asian (EAS) AF: 0.0947 AC: 2553 AN: 26946

South Asian (SAS) AF: 0.0886 AC: 3473 AN: 39194

European-Finnish (FIN) AF: 0.160 AC: 3785 AN: 23696

Middle Eastern (MID) AF: 0.0438 AC: 73 AN: 1668

European-Non Finnish (NFE) AF: 0.110 AC: 24886 AN: 225492

Other (OTH) AF: 0.107 AC: 2380 AN: 22226

GnomAD4 genome AF: 0.101 AC: 15377 AN: 152298 Hom.: 994 Cov.: 34 AF XY: 0.104 AC XY: 7723 AN XY: 74476

African (AFR) AF: 0.0484 AC: 2014 AN: 41576

American (AMR) AF: 0.182 AC: 2791 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0700 AC: 243 AN: 3472

East Asian (EAS) AF: 0.102 AC: 527 AN: 5178

South Asian (SAS) AF: 0.0968 AC: 467 AN: 4824

European-Finnish (FIN) AF: 0.163 AC: 1727 AN: 10614

Middle Eastern (MID) AF: 0.0342 AC: 10 AN: 292

European-Non Finnish (NFE) AF: 0.107 AC: 7299 AN: 68016

Other (OTH) AF: 0.106 AC: 224 AN: 2116

Alfa AF: 0.105 Hom.: 760

Bravo AF: 0.105

Asia WGS AF: 0.111 AC: 385 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.3
DANN	Benign	0.84
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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: rs3751954; hg19: chr17-77753485;