Genetic Variant HUS1B:p.Arg143Arg (chr6-656518-G-T) – ACMG Classification: Likely_benign (-3 pts)

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2BP4_StrongBP7

The NM_148959.4(HUS1B):c.427C>A(p.Arg143Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,453,068 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

HUS1B
NM_148959.4 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0460

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]

HUS1B links:

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)

EXOC2 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.88).

BP7

Synonymous conserved (PhyloP=0.046 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUS1B	NM_148959.4 link	c.427C>A	p.Arg143Arg	synonymous_variant	Exon 1 of 1	ENST00000380907.3	NP_683762.2	Q8NHY5
EXOC2	NM_018303.6 link	c.-43-18657C>A		intron_variant	Intron 1 of 27	ENST00000230449.9	NP_060773.3	Q96KP1A0A024QZT2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HUS1B	ENST00000380907.3 link	c.427C>A	p.Arg143Arg	synonymous_variant	Exon 1 of 1	6	NM_148959.4	ENSP00000370293.2	Q8NHY5
EXOC2	ENST00000230449.9 link	c.-43-18657C>A		intron_variant	Intron 1 of 27	1	NM_018303.6	ENSP00000230449.4	Q96KP1
EXOC2	ENST00000443083.5 link	c.-44+645C>A		intron_variant	Intron 3 of 5	3		ENSP00000406400.1	Q2MDF5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.88e-7

AC:

AN:

1453068

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

722632

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44552

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25942

East Asian (EAS)

AF:

0.00

AC:

AN:

39628

South Asian (SAS)

AF:

0.00

AC:

AN:

85886

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47840

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

9.01e-7

AC:

AN:

1109882

Other (OTH)

AF:

0.00

AC:

AN:

60170

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.76

(source)

DANN

Benign

0.79

PhyloP100

0.046

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over