Genetic Variant DISP2:p.Pro20Leu (chr15-40358380-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_033510.3(DISP2):c.59C>T(p.Pro20Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000822 in 1,216,404 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 8.2e-7 ( 0 hom. )

Consequence

DISP2
NM_033510.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.349

Variant links:

Genes affected

DISP2 (HGNC:19712): (dispatched RND transporter family member 2) This gene is one of two human homologs of a segment-polarity gene known as dispatched identified in Drosophila. The product of this gene may be required for normal Hedgehog (Hh) signaling during embryonic pattern formation. [provided by RefSeq, Jan 2017]

DISP2 links:

ENSG00000289148 (HGNC:):

ENSG00000289148 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06722921).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DISP2	NM_033510.3 link	c.59C>T	p.Pro20Leu	missense_variant	Exon 1 of 8	ENST00000267889.5	NP_277045.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DISP2	ENST00000267889.5 link	c.59C>T	p.Pro20Leu	missense_variant	Exon 1 of 8	1	NM_033510.3	ENSP00000267889.3		A7MBM2
ENSG00000289148	ENST00000686739.1 link	n.-243G>A		upstream_gene_variant

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

8.22e-7

AC:

AN:

1216404

Hom.:

Cov.:

AF XY:

0.00000168

AC XY:

AN XY:

594596

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000184

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 19, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.59C>T (p.P20L) alteration is located in exon 1 (coding exon 1) of the DISP2 gene. This alteration results from a C to T substitution at nucleotide position 59, causing the proline (P) at amino acid position 20 to be replaced by a leucine (L). 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

0.075

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.21

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.0033

LIST_S2

Benign

0.54

M_CAP

Benign

0.069

MetaRNN

Benign

0.067

MetaSVM

Benign

-0.98

MutationAssessor

Benign

1.2

PrimateAI

Uncertain

0.56

PROVEAN

Benign

-1.4

REVEL

Benign

0.030

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

0.0030

Vest4

0.10

MutPred

0.16

Loss of catalytic residue at G19 (P = 0.1183);

MVP

0.095

MPC

0.39

ClinPred

0.49

GERP RS

0.30

Varity_R

0.056

gMVP

0.066

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over