NM_148959.4:c.529A>G

Variant names:

• chr6-656416-T-C
• rs150422154
• NM_148959.4:c.529A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_148959.4(HUS1B):​c.529A>G​(p.Ser177Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00123 in 1,614,050 control chromosomes in the GnomAD database, including 23 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0068 (13 hom., cov: 33)
  • Exomes 𝑓: 0.00065 (10 hom.)
• Consequence: HUS1B NM_148959.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.77
• Publications: 2 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=0.003237754).
• BP6: Variant 6-656416-T-C is Benign according to our data. Variant chr6-656416-T-C is described in ClinVar as [Benign]. Clinvar id is 768058.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00678 (1033/152344) while in subpopulation AFR AF = 0.0237 (984/41590). AF 95% confidence interval is 0.0224. There are 13 homozygotes in GnomAd4. There are 498 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUS1B	NM_148959.4	c.529A>G	p.Ser177Gly	missense_variant	Exon 1 of 1	ENST00000380907.3	NP_683762.2
EXOC2	NM_018303.6	c.-43-18555A>G		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.529A>G	p.Ser177Gly	missense_variant	Exon 1 of 1	6	NM_148959.4	ENSP00000370293.2
EXOC2	ENST00000230449.9	c.-43-18555A>G		intron_variant	Intron 1 of 27	1	NM_018303.6	ENSP00000230449.4
EXOC2	ENST00000443083.5	c.-44+747A>G		intron_variant	Intron 3 of 5	3		ENSP00000406400.1

Frequencies

GnomAD3 genomes AF: 0.00675 AC: 1027 AN: 152226 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.0236

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

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: 0.0000147

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00164 AC: 410 AN: 250140 AF XY: 0.00127

Gnomad AFR exome AF: 0.0232

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000885

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000653 AC: 955 AN: 1461706 Hom.: 10 Cov.: 34 AF XY: 0.000579 AC XY: 421 AN XY: 727118

African (AFR) AF: 0.0240 AC: 802 AN: 33478

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53356

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5766

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1111910

Other (OTH) AF: 0.00137 AC: 83 AN: 60390

GnomAD4 genome AF: 0.00678 AC: 1033 AN: 152344 Hom.: 13 Cov.: 33 AF XY: 0.00668 AC XY: 498 AN XY: 74500

African (AFR) AF: 0.0237 AC: 984 AN: 41590

American (AMR) AF: 0.00242 AC: 37 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00521 AC: 11 AN: 2112

Alfa AF: 0.00144 Hom.: 3

Bravo AF: 0.00752

ESP6500AA AF: 0.0186 AC: 82

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00204 AC: 248

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

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

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.75	T
BayesDel_noAF	Benign	-0.84
CADD	Benign	0.27
DANN	Benign	0.83
DEOGEN2	Benign	0.025	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.00028	N
LIST_S2	Benign	0.23	T
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		-2.8
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.040
Sift	Benign	0.15	T
Sift4G	Uncertain	0.033	D
Polyphen		0.0	B
Vest4		0.069
MVP		0.055
MPC		0.26
ClinPred		0.016	T
GERP RS		-7.5
Varity_R		0.11
gMVP		0.25
Mutation Taster		=96/4	polymorphism

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: rs150422154; hg19: chr6-656416;