12-50678760-G-C

Variant names:

• chr12-50678760-G-C
• rs1006854230
• NM_173602.3:c.998G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_173602.3(DIP2B):​c.998G>C​(p.Cys333Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: DIP2B NM_173602.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.93
• Publications: 1 publications found

Genes affected

DIP2B (HGNC:29284): (disco interacting protein 2 homolog B) This gene encodes a member of the disco-interacting protein homolog 2 protein family. The encoded protein contains a binding site for the transcriptional regulator DNA methyltransferase 1 associated protein 1 as well as AMP-binding sites. The presence of these sites suggests that the encoded protein may participate in DNA methylation. This gene is located near a folate-sensitive fragile site, and CGG-repeat expansion in the promoter of this gene which affects transcription has been detected in individuals containing this fragile site on chromosome 12. [provided by RefSeq, Aug 2011]

DIP2B Gene-Disease associations (from GenCC):

• intellectual disability, FRA12A type

  Inheritance: AD, Unknown Classification: LIMITED, NO_KNOWN Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13777104).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_173602.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIP2B	NM_173602.3	MANE Select	c.998G>C	p.Cys333Ser	missense	Exon 8 of 38	NP_775873.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DIP2B	ENST00000301180.10	TSL:5 MANE Select	c.998G>C	p.Cys333Ser	missense	Exon 8 of 38	ENSP00000301180.5
	DIP2B	ENST00000546719.1	TSL:1	n.775G>C		non_coding_transcript_exon	Exon 7 of 7
	DIP2B	ENST00000549620.5	TSL:1	n.1154G>C		non_coding_transcript_exon	Exon 8 of 8

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461888 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 09, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	22
DANN	Benign	0.53
DEOGEN2	Benign	0.019	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.22
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.86	D
M_CAP	Benign	0.0029	T
MetaRNN	Benign	0.14	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		4.9
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	1.5	N
REVEL	Benign	0.082
Sift	Benign	0.96	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.35
MutPred		0.40		Gain of catalytic residue at L329 (P = 0)
MVP		0.043
MPC		0.42
ClinPred		0.54	D
GERP RS		3.8
Varity_R		0.24
gMVP		0.73
Mutation Taster		=86/14	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.18		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: rs1006854230; hg19: chr12-51072543;