6-656539-C-A

Variant names:

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_148959.4(HUS1B):c.406G>T(p.Val136Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0018 in 1,601,012 control chromosomes in the GnomAD database, including 44 homozygotes. 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 Benign (★).

Frequency

Genomes: 𝑓 0.0095 ( 25 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 19 hom. )

Consequence

HUS1B
NM_148959.4 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.08

Publications

4 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010014981).

BP6

Variant 6-656539-C-A is Benign according to our data. Variant chr6-656539-C-A is described in ClinVar as [Benign]. Clinvar id is 792029.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00948 (1445/152350) while in subpopulation AFR AF = 0.0331 (1375/41580). AF 95% confidence interval is 0.0316. There are 25 homozygotes in GnomAd4. There are 685 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 25 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUS1B	NM_148959.4 link	c.406G>T	p.Val136Leu	missense_variant	Exon 1 of 1	ENST00000380907.3	NP_683762.2	Q8NHY5
EXOC2	NM_018303.6 link	c.-43-18678G>T		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.406G>T	p.Val136Leu	missense_variant	Exon 1 of 1	6	NM_148959.4	ENSP00000370293.2	Q8NHY5
EXOC2	ENST00000230449.9 link	c.-43-18678G>T		intron_variant	Intron 1 of 27	1	NM_018303.6	ENSP00000230449.4	Q96KP1
EXOC2	ENST00000443083.5 link	c.-44+624G>T		intron_variant	Intron 3 of 5	3		ENSP00000406400.1	Q2MDF5

Frequencies

GnomAD3 genomes

AF:

0.00943

AC:

1435

AN:

152232

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0329

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00320

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00637

Gnomad NFE

AF:

0.000132

Gnomad OTH

AF:

0.00526

GnomAD2 exomes

AF:

0.00258

AC:

606

AN:

234922

AF XY:

0.00196

show subpopulations

Gnomad AFR exome

AF:

0.0362

Gnomad AMR exome

AF:

0.00167

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000661

Gnomad OTH exome

AF:

0.00103

GnomAD4 exome

AF:

0.000996

AC:

1443

AN:

1448662

Hom.:

Cov.:

AF XY:

0.000856

AC XY:

616

AN XY:

719652

show subpopulations

African (AFR)

AF:

0.0343

AC:

1140

AN:

33278

American (AMR)

AF:

0.00189

AC:

AN:

44338

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25758

East Asian (EAS)

AF:

0.00

AC:

AN:

39534

South Asian (SAS)

AF:

0.000117

AC:

AN:

85486

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47666

Middle Eastern (MID)

AF:

0.00314

AC:

AN:

5740

European-Non Finnish (NFE)

AF:

0.0000416

AC:

AN:

1106922

Other (OTH)

AF:

0.00242

AC:

145

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

182

273

364

455

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00948

AC:

1445

AN:

152350

Hom.:

Cov.:

AF XY:

0.00919

AC XY:

685

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.0331

AC:

1375

AN:

41580

American (AMR)

AF:

0.00314

AC:

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10630

Middle Eastern (MID)

AF:

0.00685

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.000132

AC:

AN:

68036

Other (OTH)

AF:

0.00520

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

Heterozygous variant carriers

144

216

288

360

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00246

Hom.:

Bravo

AF:

0.0108

ESP6500AA

AF:

0.0234

AC:

102

ESP6500EA

AF:

0.000235

AC:

ExAC

AF:

0.00298

AC:

356

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

Mar 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.38

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.025

Eigen

Benign

-0.40

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.13

LIST_S2

Benign

0.52

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.1

PhyloP100

1.1

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.5

REVEL

Benign

0.13

Sift

Benign

0.073

Sift4G

Uncertain

0.013

Polyphen

0.94

Vest4

0.32

MutPred

0.91

Loss of sheet (P = 0.1158);

MVP

0.13

MPC

0.31

ClinPred

0.062

GERP RS

2.6

Varity_R

0.33

gMVP

0.54

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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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6-656539-C-A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over