5-39376839-C-A

Position:

• chr5-39376839-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001343.4(DAB2):​c.1948G>T​(p.Asp650Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: DAB2 NM_001343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.43

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25222418).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
DAB2	NM_001343.4	c.1948G>T	p.Asp650Tyr	missense_variant	12/15	ENST00000320816.11	NP_001334.2
DAB2	NM_001244871.2	c.1885G>T	p.Asp629Tyr	missense_variant	11/14		NP_001231800.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
DAB2	ENST00000320816.11	c.1948G>T	p.Asp650Tyr	missense_variant	12/15	1	NM_001343.4	ENSP00000313391	P3
DAB2	ENST00000509337.5	c.1885G>T	p.Asp629Tyr	missense_variant	10/13	1		ENSP00000426245	A1
DAB2	ENST00000545653.5	c.1885G>T	p.Asp629Tyr	missense_variant	11/14	5		ENSP00000439919	A1
DAB2	ENST00000339788.10	c.1294G>T	p.Asp432Tyr	missense_variant	11/14	5		ENSP00000345508

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

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

Dec 22, 2023

The c.1948G>T (p.D650Y) alteration is located in exon 12 (coding exon 11) of the DAB2 gene. This alteration results from a G to T substitution at nucleotide position 1948, causing the aspartic acid (D) at amino acid position 650 to be replaced by a tyrosine (Y). 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	0.28
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.52	.;.;D;.
Eigen	Uncertain	0.36
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.94	D;D;D;.
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.3	.;.;L;.
MutationTaster	Benign	0.99	N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-2.1	N;N;N;N
REVEL	Benign	0.055
Sift	Uncertain	0.018	D;D;D;D
Sift4G	Uncertain	0.041	D;D;D;D
Polyphen		0.85	P;.;P;P
Vest4		0.30
MutPred		0.41		.;.;Loss of helix (P = 3e-04);.;
MVP		0.39
MPC		0.32
ClinPred		0.91	D
GERP RS		5.1
Varity_R		0.17
gMVP		0.20

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-39376941;