rs700241

Positions:

• chr5-39377030-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000320816.11(DAB2):​c.1757C>T​(p.Thr586Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0185 in 1,614,058 control chromosomes in the GnomAD database, including 797 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.044 (329 hom., cov: 32)
  • Exomes 𝑓: 0.016 (468 hom.)
• Consequence: DAB2 ENST00000320816.11 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.71

Genes affected

DAB2 (HGNC:2662): (DAB adaptor protein 2) This gene encodes a mitogen-responsive phosphoprotein. It is expressed in normal ovarian epithelial cells, but is down-regulated or absent from ovarian carcinoma cell lines, suggesting its role as a tumor suppressor. This protein binds to the SH3 domains of GRB2, an adaptor protein that couples tyrosine kinase receptors to SOS (a guanine nucleotide exchange factor for Ras), via its C-terminal proline-rich sequences, and may thus modulate growth factor/Ras pathways by competing with SOS for binding to GRB2. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017542243).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAB2	NM_001343.4	c.1757C>T	p.Thr586Ile	missense_variant	12/15	ENST00000320816.11	NP_001334.2
DAB2	NM_001244871.2	c.1694C>T	p.Thr565Ile	missense_variant	11/14		NP_001231800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAB2	ENST00000320816.11	c.1757C>T	p.Thr586Ile	missense_variant	12/15	1	NM_001343.4	ENSP00000313391	P3
DAB2	ENST00000509337.5	c.1694C>T	p.Thr565Ile	missense_variant	10/13	1		ENSP00000426245	A1
DAB2	ENST00000545653.5	c.1694C>T	p.Thr565Ile	missense_variant	11/14	5		ENSP00000439919	A1
DAB2	ENST00000339788.10	c.1103C>T	p.Thr368Ile	missense_variant	11/14	5		ENSP00000345508

Frequencies

GnomAD3 genomes AF: 0.0438 AC: 6658 AN: 152074 Hom.: 328 Cov.: 32

Gnomad AFR AF: 0.121

Gnomad AMI AF: 0.00548

Gnomad AMR AF: 0.0231

Gnomad ASJ AF: 0.00346

Gnomad EAS AF: 0.0385

Gnomad SAS AF: 0.0282

Gnomad FIN AF: 0.00188

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0125

Gnomad OTH AF: 0.0345

GnomAD3 exomes AF: 0.0221 AC: 5549 AN: 251164 Hom.: 178 AF XY: 0.0202 AC XY: 2739 AN XY: 135738

Gnomad AFR exome AF: 0.125

Gnomad AMR exome AF: 0.0127

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.0397

Gnomad SAS exome AF: 0.0249

Gnomad FIN exome AF: 0.00162

Gnomad NFE exome AF: 0.0126

Gnomad OTH exome AF: 0.0165

GnomAD4 exome AF: 0.0159 AC: 23198 AN: 1461866 Hom.: 468 Cov.: 34 AF XY: 0.0158 AC XY: 11454 AN XY: 727238

Gnomad4 AFR exome AF: 0.124

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.00165

Gnomad4 EAS exome AF: 0.0301

Gnomad4 SAS exome AF: 0.0242

Gnomad4 FIN exome AF: 0.00217

Gnomad4 NFE exome AF: 0.0123

Gnomad4 OTH exome AF: 0.0199

GnomAD4 genome AF: 0.0439 AC: 6674 AN: 152192 Hom.: 329 Cov.: 32 AF XY: 0.0417 AC XY: 3102 AN XY: 74396

Gnomad4 AFR AF: 0.121

Gnomad4 AMR AF: 0.0233

Gnomad4 ASJ AF: 0.00346

Gnomad4 EAS AF: 0.0384

Gnomad4 SAS AF: 0.0282

Gnomad4 FIN AF: 0.00188

Gnomad4 NFE AF: 0.0125

Gnomad4 OTH AF: 0.0341

Alfa AF: 0.0178 Hom.: 194

Bravo AF: 0.0491

TwinsUK AF: 0.0129 AC: 48

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.121 AC: 534

ESP6500EA AF: 0.0126 AC: 108

ExAC AF: 0.0241 AC: 2930

Asia WGS AF: 0.0430 AC: 151 AN: 3478

EpiCase AF: 0.0123

EpiControl AF: 0.0136

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Benign	0.97
DEOGEN2	Benign	0.39	.;.;T;.
Eigen	Benign	-0.43
Eigen_PC	Benign	-0.30
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.37	T;T;T;.
MetaRNN	Benign	0.0018	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	.;.;L;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.036	D;T;T;D
Sift4G	Uncertain	0.043	D;T;D;D
Polyphen		0.041	B;.;B;B
Vest4		0.067
MPC		0.073
ClinPred		0.0055	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.069
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs700241; hg19: chr5-39377132;