Variant 19-12766107-G-T details in Genebe, Genetics Data Aggregator

Variant summary

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

The NM_013312.3(HOOK2):c.1507C>A(p.His503Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000412 in 1,602,332 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H503Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000039 ( 0 hom. )

Consequence

HOOK2
NM_013312.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.54

Variant links:

Genes affected

HOOK2 (HGNC:19885): (hook microtubule tethering protein 2) Hook proteins are cytosolic coiled-coil proteins that contain conserved N-terminal domains, which attach to microtubules, and more divergent C-terminal domains, which mediate binding to organelles. The Drosophila Hook protein is a component of the endocytic compartment.[supplied by OMIM, Apr 2004]

HOOK2 links:

Genome browser will be placed here

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=0.033287376).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HOOK2	NM_013312.3 linkuse as main transcript	c.1507C>A	p.His503Asn	missense_variant	15/23	ENST00000397668.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HOOK2	ENST00000397668.8 linkuse as main transcript	c.1507C>A	p.His503Asn	missense_variant	15/23	1	NM_013312.3	A1	Q96ED9-1

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000379

AC:

AN:

237604

Hom.:

AF XY:

0.0000384

AC XY:

AN XY:

130346

show subpopulations

Gnomad AFR exome

AF:

0.0000679

Gnomad AMR exome

AF:

0.0000875

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000273

Gnomad OTH exome

AF:

0.000340

GnomAD4 exome

AF:

0.0000386

AC:

AN:

1450122

Hom.:

Cov.:

AF XY:

0.0000430

AC XY:

AN XY:

721502

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000673

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000396

Gnomad4 OTH exome

AF:

0.0000997

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000965

Gnomad4 AMR

AF:

0.000196

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000831

ExAC

AF:

0.0000332

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 02, 2021

The c.1507C>A (p.H503N) alteration is located in exon 15 (coding exon 15) of the HOOK2 gene. This alteration results from a C to A substitution at nucleotide position 1507, causing the histidine (H) at amino acid position 503 to be replaced by an asparagine (N). 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

-0.49

BayesDel_noAF

Benign

-0.75

Cadd

Benign

Dann

Benign

0.94

DEOGEN2

Benign

0.0032

T;.

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.045

FATHMM_MKL

Benign

0.33

LIST_S2

Benign

0.80

T;T

M_CAP

Benign

0.0095

MetaRNN

Benign

0.033

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.11

N;N

MutationTaster

Benign

0.99

N;N

PrimateAI

Uncertain

0.58

PROVEAN

Benign

0.98

N;N

REVEL

Benign

0.069

Sift

Benign

1.0

T;T

Sift4G

Benign

0.99

T;T

Polyphen

0.0

B;B

Vest4

0.13

MutPred

0.35

Loss of catalytic residue at L505 (P = 0.096);Loss of catalytic residue at L505 (P = 0.096);

MVP

0.22

MPC

0.27

ClinPred

0.030

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.088

gMVP

0.12

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