chr12-50678822-T-C

Position:

• chr12-50678822-T-C

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_173602.3(DIP2B):​c.1060T>C​(p.Ser354Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00168 in 1,614,212 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0017 (7 hom.)
• Consequence: DIP2B NM_173602.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 4.10

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 -9 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=0.009845793).
• BP6: Variant 12-50678822-T-C is Benign according to our data. Variant chr12-50678822-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 445445.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr12-50678822-T-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd4 at 169 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DIP2B	NM_173602.3	c.1060T>C	p.Ser354Pro	missense_variant	8/38	ENST00000301180.10	NP_775873.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DIP2B	ENST00000301180.10	c.1060T>C	p.Ser354Pro	missense_variant	8/38	5	NM_173602.3	ENSP00000301180	P1
DIP2B	ENST00000546719.1	n.837T>C		non_coding_transcript_exon_variant	7/7	1
DIP2B	ENST00000549620.5	n.1216T>C		non_coding_transcript_exon_variant	8/8	1

Frequencies

GnomAD3 genomes AF: 0.00111 AC: 169 AN: 152214 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00197

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000871 AC: 219 AN: 251424 Hom.: 0 AF XY: 0.000912 AC XY: 124 AN XY: 135894

Gnomad AFR exome AF: 0.000615

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00155

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.00174 AC: 2545 AN: 1461880 Hom.: 7 Cov.: 30 AF XY: 0.00174 AC XY: 1266 AN XY: 727244

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000268

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000626

Gnomad4 FIN exome AF: 0.0000562

Gnomad4 NFE exome AF: 0.00215

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00111 AC: 169 AN: 152332 Hom.: 0 Cov.: 31 AF XY: 0.000926 AC XY: 69 AN XY: 74496

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0000942

Gnomad4 NFE AF: 0.00197

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00173 Hom.: 2

Bravo AF: 0.00111

TwinsUK AF: 0.00216 AC: 8

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.00221 AC: 19

ExAC AF: 0.000791 AC: 96

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00185

EpiControl AF: 0.00113

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

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

Jul 21, 2017

- -

DIP2B-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 25, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.037
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	17
DANN	Benign	0.31
DEOGEN2	Benign	0.023	T
Eigen	Benign	-0.73
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0077	T
MetaRNN	Benign	0.0098	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.4	N
MutationTaster	Benign	0.83	D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	5.8	N
REVEL	Benign	0.073
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.35
MVP		0.043
MPC		0.44
ClinPred		0.0038	T
GERP RS		2.7
Varity_R		0.073
gMVP		0.71

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: rs117722674; hg19: chr12-51072605;