6-656555-G-T

Variant names:

• chr6-656555-G-T
• rs1766848
• NM_148959.4:c.390C>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_148959.4(HUS1B):​c.390C>A​(p.His130Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0941 in 1,596,410 control chromosomes in the GnomAD database, including 7,562 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.078 (620 hom., cov: 33)
  • Exomes 𝑓: 0.096 (6942 hom.)
• Consequence: HUS1B NM_148959.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0510
• Publications: 25 publications found

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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0033777952).
• BP6: Variant 6-656555-G-T is Benign according to our data. Variant chr6-656555-G-T is described in ClinVar as [Benign]. Clinvar id is 1178804.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.117 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUS1B	NM_148959.4	c.390C>A	p.His130Gln	missense_variant	Exon 1 of 1	ENST00000380907.3	NP_683762.2
EXOC2	NM_018303.6	c.-43-18694C>A		intron_variant	Intron 1 of 27	ENST00000230449.9	NP_060773.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HUS1B	ENST00000380907.3	c.390C>A	p.His130Gln	missense_variant	Exon 1 of 1	6	NM_148959.4	ENSP00000370293.2
EXOC2	ENST00000230449.9	c.-43-18694C>A		intron_variant	Intron 1 of 27	1	NM_018303.6	ENSP00000230449.4
EXOC2	ENST00000443083.5	c.-44+608C>A		intron_variant	Intron 3 of 5	3		ENSP00000406400.1

Frequencies

GnomAD3 genomes AF: 0.0780 AC: 11878 AN: 152190 Hom.: 620 Cov.: 33

Gnomad AFR AF: 0.0213

Gnomad AMI AF: 0.102

Gnomad AMR AF: 0.121

Gnomad ASJ AF: 0.0878

Gnomad EAS AF: 0.0540

Gnomad SAS AF: 0.0586

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0955

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.0688

GnomAD2 exomes AF: 0.0913 AC: 21173 AN: 232016 AF XY: 0.0895

Gnomad AFR exome AF: 0.0181

Gnomad AMR exome AF: 0.134

Gnomad ASJ exome AF: 0.0795

Gnomad EAS exome AF: 0.0533

Gnomad FIN exome AF: 0.106

Gnomad NFE exome AF: 0.102

Gnomad OTH exome AF: 0.0969

GnomAD4 exome AF: 0.0958 AC: 138384 AN: 1444102 Hom.: 6942 Cov.: 35 AF XY: 0.0952 AC XY: 68212 AN XY: 716774

African (AFR) AF: 0.0169 AC: 561 AN: 33178

American (AMR) AF: 0.130 AC: 5696 AN: 43968

Ashkenazi Jewish (ASJ) AF: 0.0798 AC: 2032 AN: 25476

East Asian (EAS) AF: 0.0578 AC: 2280 AN: 39438

South Asian (SAS) AF: 0.0595 AC: 5045 AN: 84778

European-Finnish (FIN) AF: 0.106 AC: 5061 AN: 47530

Middle Eastern (MID) AF: 0.0727 AC: 415 AN: 5710

European-Non Finnish (NFE) AF: 0.102 AC: 112238 AN: 1104354

Other (OTH) AF: 0.0847 AC: 5056 AN: 59670

GnomAD4 genome AF: 0.0780 AC: 11874 AN: 152308 Hom.: 620 Cov.: 33 AF XY: 0.0792 AC XY: 5897 AN XY: 74476

African (AFR) AF: 0.0213 AC: 884 AN: 41586

American (AMR) AF: 0.121 AC: 1854 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0878 AC: 305 AN: 3472

East Asian (EAS) AF: 0.0538 AC: 278 AN: 5172

South Asian (SAS) AF: 0.0595 AC: 287 AN: 4824

European-Finnish (FIN) AF: 0.106 AC: 1126 AN: 10614

Middle Eastern (MID) AF: 0.0959 AC: 28 AN: 292

European-Non Finnish (NFE) AF: 0.101 AC: 6876 AN: 68018

Other (OTH) AF: 0.0676 AC: 143 AN: 2114

Alfa AF: 0.0938 Hom.: 2032

Bravo AF: 0.0747

TwinsUK AF: 0.102 AC: 380

ALSPAC AF: 0.0978 AC: 377

ESP6500AA AF: 0.0189 AC: 83

ESP6500EA AF: 0.0934 AC: 799

ExAC AF: 0.0860 AC: 10253

Asia WGS AF: 0.0540 AC: 186 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Apr 20, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 30679340) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.90
DEOGEN2	Benign	0.082	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.33	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.8	M
PhyloP100		0.051
PrimateAI	Benign	0.45	T
PROVEAN	Pathogenic	-6.7	D
REVEL	Benign	0.21
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0080	D
Polyphen		1.0	D
Vest4		0.12
MutPred		0.93		Loss of catalytic residue at L132 (P = 0.0562);
MPC		0.88
ClinPred		0.10	T
GERP RS		-2.9
Varity_R		0.74
gMVP		0.81
Mutation Taster		=94/6	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1766848; hg19: chr6-656555; COSMIC: COSV57860647;