5-39376785-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001343.4(DAB2):c.2002G>A(p.Ala668Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,614,102 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (1 hom.)
• Consequence: DAB2 NM_001343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.46

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08011815).
• BS2: High AC in GnomAd at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
DAB2	NM_001343.4	c.2002G>A	p.Ala668Thr	missense_variant	12/15	ENST00000320816.11
DAB2	NM_001244871.2	c.1939G>A	p.Ala647Thr	missense_variant	11/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
DAB2	ENST00000320816.11	c.2002G>A	p.Ala668Thr	missense_variant	12/15	1	NM_001343.4	P3
DAB2	ENST00000509337.5	c.1939G>A	p.Ala647Thr	missense_variant	10/13	1		A1
DAB2	ENST00000545653.5	c.1939G>A	p.Ala647Thr	missense_variant	11/14	5		A1
DAB2	ENST00000339788.10	c.1348G>A	p.Ala450Thr	missense_variant	11/14	5

Frequencies

GnomAD3 genomes AF: 0.000158 AC: 24 AN: 152184 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00111

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000247 AC: 62 AN: 250958 Hom.: 1 AF XY: 0.000229 AC XY: 31 AN XY: 135650

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00110

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000794

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1461800 Hom.: 1 Cov.: 33 AF XY: 0.000143 AC XY: 104 AN XY: 727202

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.00116

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000118

Gnomad4 OTH exome AF: 0.000282

GnomAD4 genome AF: 0.000158 AC: 24 AN: 152302 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74464

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00111

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.000340

ExAC AF: 0.000132 AC: 16

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 20, 2021

The c.2002G>A (p.A668T) alteration is located in exon 12 (coding exon 11) of the DAB2 gene. This alteration results from a G to A substitution at nucleotide position 2002, causing the alanine (A) at amino acid position 668 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	19
Dann	Uncertain	1.0
Eigen	Benign	0.079
Eigen_PC	Benign	-0.041
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.93	D;D;D;.
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.080	T;T;T;T
MetaSVM	Benign	-0.65	T
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.5	N;N;N;N
REVEL	Benign	0.14
Sift	Uncertain	0.0050	D;D;D;D
Sift4G	Uncertain	0.013	D;D;D;D
Polyphen		0.98	D;.;D;D
Vest4		0.48
MVP		0.54
MPC		0.24
ClinPred		0.36	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.35

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: rs199699595; hg19: chr5-39376887; COSMIC: COSV57914495; COSMIC: COSV57914495;