5-39377157-C-T

Position:

• chr5-39377157-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001343.4(DAB2):​c.1630G>A​(p.Val544Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00431 in 1,614,086 control chromosomes in the GnomAD database, including 32 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0045 (28 hom.)
• Consequence: DAB2 NM_001343.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.183

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 -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002797097).
• BP6: Variant 5-39377157-C-T is Benign according to our data. Variant chr5-39377157-C-T is described in ClinVar as [Benign]. Clinvar id is 719334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 437 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAB2	NM_001343.4	c.1630G>A	p.Val544Ile	missense_variant	12/15	ENST00000320816.11	NP_001334.2
DAB2	NM_001244871.2	c.1567G>A	p.Val523Ile	missense_variant	11/14		NP_001231800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAB2	ENST00000320816.11	c.1630G>A	p.Val544Ile	missense_variant	12/15	1	NM_001343.4	ENSP00000313391	P3
DAB2	ENST00000509337.5	c.1567G>A	p.Val523Ile	missense_variant	10/13	1		ENSP00000426245	A1
DAB2	ENST00000545653.5	c.1567G>A	p.Val523Ile	missense_variant	11/14	5		ENSP00000439919	A1
DAB2	ENST00000339788.10	c.976G>A	p.Val326Ile	missense_variant	11/14	5		ENSP00000345508

Frequencies

GnomAD3 genomes AF: 0.00287 AC: 437 AN: 152126 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.000821

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.0190

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00910

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00379

Gnomad OTH AF: 0.00431

GnomAD3 exomes AF: 0.00387 AC: 971 AN: 250598 Hom.: 4 AF XY: 0.00401 AC XY: 543 AN XY: 135382

Gnomad AFR exome AF: 0.000985

Gnomad AMR exome AF: 0.00177

Gnomad ASJ exome AF: 0.0174

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00666

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00425

Gnomad OTH exome AF: 0.00474

GnomAD4 exome AF: 0.00446 AC: 6526 AN: 1461842 Hom.: 28 Cov.: 34 AF XY: 0.00448 AC XY: 3258 AN XY: 727220

Gnomad4 AFR exome AF: 0.000687

Gnomad4 AMR exome AF: 0.00165

Gnomad4 ASJ exome AF: 0.0183

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.00664

Gnomad4 FIN exome AF: 0.000356

Gnomad4 NFE exome AF: 0.00454

Gnomad4 OTH exome AF: 0.00475

GnomAD4 genome AF: 0.00287 AC: 437 AN: 152244 Hom.: 4 Cov.: 32 AF XY: 0.00285 AC XY: 212 AN XY: 74432

Gnomad4 AFR AF: 0.000819

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.0190

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00911

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00379

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00457 Hom.: 5

Bravo AF: 0.00271

TwinsUK AF: 0.00431 AC: 16

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.00159 AC: 7

ESP6500EA AF: 0.00326 AC: 28

ExAC AF: 0.00362 AC: 439

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00404

EpiControl AF: 0.00427

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jul 26, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.72
CADD	Benign	6.3
DANN	Benign	0.55
DEOGEN2	Benign	0.29	.;.;T;.
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.064	N
LIST_S2	Benign	0.64	T;T;T;.
M_CAP	Benign	0.0039	T
MetaRNN	Benign	0.0028	T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.29	.;.;N;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.020	N;N;N;N
REVEL	Benign	0.025
Sift	Benign	0.50	T;T;T;T
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0050	B;.;B;B
Vest4		0.060
MVP		0.20
MPC		0.055
ClinPred		0.0020	T
GERP RS		-6.1
Varity_R		0.019
gMVP		0.055

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: rs61755342; hg19: chr5-39377259; COSMIC: COSV57918851; COSMIC: COSV57918851;