6-656466-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_148959.4(HUS1B):​c.479C>A​(p.Pro160Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000657 in 152,248 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P160L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Consequence

HUS1B
NM_148959.4 missense

Scores

3
5
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

0 publications found
Variant links:
Genes affected
HUS1B (HGNC:16485): (HUS1 checkpoint clamp component B) The protein encoded by this gene is most closely related to HUS1, a component of a cell cycle checkpoint protein complex involved in cell cycle arrest in response to DNA damage. This protein can interact with the check point protein RAD1 but not with RAD9. Overexpression of this protein has been shown to induce cell death, which suggests a related but distinct role of this protein, as compared to the HUS1. [provided by RefSeq, Jul 2008]
EXOC2 (HGNC:24968): (exocyst complex component 2) The protein encoded by this gene is a component of the exocyst complex, a multi-protein complex essential for the polarized targeting of exocytic vesicles to specific docking sites on the plasma membrane. Though best characterized in yeast, the component proteins and the functions of the exocyst complex have been demonstrated to be highly conserved in higher eukaryotes. At least eight components of the exocyst complex, including this protein, are found to interact with the actin cytoskeletal remodeling and vesicle transport machinery. This interaction has been shown to mediate filopodia formation in fibroblasts. This protein has been shown to interact with the Ral subfamily of GTPases and thereby mediate exocytosis by tethering vesicles to the plasma membrane. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jul 2012]
EXOC2 Gene-Disease associations (from GenCC):
  • complex neurodevelopmental disorder
    Inheritance: AR Classification: LIMITED Submitted by: ClinGen
  • neurodevelopmental disorder with dysmorphic facies and cerebellar hypoplasia
    Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.975

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
HUS1BNM_148959.4 linkc.479C>A p.Pro160Gln missense_variant Exon 1 of 1 ENST00000380907.3 NP_683762.2 Q8NHY5
EXOC2NM_018303.6 linkc.-43-18605C>A intron_variant Intron 1 of 27 ENST00000230449.9 NP_060773.3 Q96KP1A0A024QZT2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
HUS1BENST00000380907.3 linkc.479C>A p.Pro160Gln missense_variant Exon 1 of 1 6 NM_148959.4 ENSP00000370293.2 Q8NHY5
EXOC2ENST00000230449.9 linkc.-43-18605C>A intron_variant Intron 1 of 27 1 NM_018303.6 ENSP00000230449.4 Q96KP1
EXOC2ENST00000443083.5 linkc.-44+697C>A intron_variant Intron 3 of 5 3 ENSP00000406400.1 Q2MDF5

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152248
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
Cov.:
34
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152248
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
AN XY:
74378
show subpopulations
African (AFR)
AF:
0.0000241
AC:
1
AN:
41474
American (AMR)
AF:
0.00
AC:
0
AN:
15288
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5196
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4838
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10620
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68040
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.83
BayesDel_addAF
Uncertain
0.036
T
BayesDel_noAF
Benign
-0.19
CADD
Benign
19
DANN
Uncertain
0.98
DEOGEN2
Benign
0.10
T
Eigen
Benign
0.14
Eigen_PC
Benign
-0.090
FATHMM_MKL
Benign
0.57
D
LIST_S2
Benign
0.33
T
M_CAP
Benign
0.0052
T
MetaRNN
Pathogenic
0.97
D
MetaSVM
Benign
-0.92
T
MutationAssessor
Uncertain
2.8
M
PhyloP100
1.1
PrimateAI
Benign
0.33
T
PROVEAN
Pathogenic
-7.4
D
REVEL
Benign
0.27
Sift
Uncertain
0.0030
D
Sift4G
Uncertain
0.010
D
Polyphen
1.0
D
Vest4
0.48
MutPred
0.81
Gain of solvent accessibility (P = 0.0137);
MVP
0.59
MPC
0.89
ClinPred
0.98
D
GERP RS
2.7
Varity_R
0.81
gMVP
0.68
Mutation Taster
=87/13
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
Details are displayed if max score is > 0.2

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

Publications

Other links and lift over

dbSNP: rs773687295; hg19: chr6-656466; API