12-50674626-G-A

Position:

• chr12-50674626-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. PP2 BP4_Strong BP6_Very_Strong BS2

The NM_173602.3(DIP2B):​c.793G>A​(p.Asp265Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00995 in 1,613,996 control chromosomes in the GnomAD database, including 105 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (6 hom., cov: 32)
  • Exomes 𝑓: 0.010 (99 hom.)
• Consequence: DIP2B NM_173602.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 9.36

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]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), DIP2B. . Gene score misZ 3.1809 (greater than the threshold 3.09). Trascript score misZ 4.0584 (greater than threshold 3.09). GenCC has associacion of gene with intellectual disability, FRA12A type.
• BP4: Computational evidence support a benign effect (MetaRNN=0.009075761).
• BP6: Variant 12-50674626-G-A is Benign according to our data. Variant chr12-50674626-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 377262.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 980 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIP2B	NM_173602.3	c.793G>A	p.Asp265Asn	missense_variant	6/38	ENST00000301180.10	NP_775873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIP2B	ENST00000301180.10	c.793G>A	p.Asp265Asn	missense_variant	6/38	5	NM_173602.3	ENSP00000301180	P1
DIP2B	ENST00000546719.1	n.570G>A		non_coding_transcript_exon_variant	5/7	1
DIP2B	ENST00000549620.5	n.949G>A		non_coding_transcript_exon_variant	6/8	1

Frequencies

GnomAD3 genomes AF: 0.00645 AC: 981 AN: 152194 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00205

Gnomad AMI AF: 0.0724

Gnomad AMR AF: 0.00425

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0106

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00605 AC: 1518 AN: 251060 Hom.: 7 AF XY: 0.00578 AC XY: 785 AN XY: 135698

Gnomad AFR exome AF: 0.00197

Gnomad AMR exome AF: 0.00420

Gnomad ASJ exome AF: 0.00189

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00356

Gnomad NFE exome AF: 0.0106

Gnomad OTH exome AF: 0.00637

GnomAD4 exome AF: 0.0103 AC: 15075 AN: 1461684 Hom.: 99 Cov.: 31 AF XY: 0.00983 AC XY: 7145 AN XY: 727122

Gnomad4 AFR exome AF: 0.00167

Gnomad4 AMR exome AF: 0.00454

Gnomad4 ASJ exome AF: 0.00222

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.00416

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.00954

GnomAD4 genome AF: 0.00643 AC: 980 AN: 152312 Hom.: 6 Cov.: 32 AF XY: 0.00573 AC XY: 427 AN XY: 74480

Gnomad4 AFR AF: 0.00202

Gnomad4 AMR AF: 0.00425

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.0106

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00913 Hom.: 11

Bravo AF: 0.00663

TwinsUK AF: 0.0108 AC: 40

ALSPAC AF: 0.0106 AC: 41

ESP6500AA AF: 0.00204 AC: 9

ESP6500EA AF: 0.0103 AC: 89

ExAC AF: 0.00619 AC: 752

Asia WGS AF: 0.000289 AC: 2 AN: 3478

EpiCase AF: 0.00862

EpiControl AF: 0.0110

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Mar 29, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.57
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.039	T
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D
MetaRNN	Benign	0.0091	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.9	L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.25
Sift	Benign	0.24	T
Sift4G	Benign	0.48	T
Polyphen		0.012	B
Vest4		0.80
MVP		0.19
MPC		0.36
ClinPred		0.025	T
GERP RS		4.6
Varity_R		0.19
gMVP		0.63

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: rs73093419; hg19: chr12-51068409; COSMIC: COSV105189907;