chr6-656541-C-G

Variant names:

• chr6-656541-C-G
• rs1484409532
• NM_148959.4:c.404G>C

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_148959.4(HUS1B):​c.404G>C​(p.Arg135Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,448,606 control chromosomes in the GnomAD database, with no homozygous occurrence. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HUS1B NM_148959.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0520
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HUS1B	NM_148959.4	c.404G>C	p.Arg135Pro	missense_variant	Exon 1 of 1	ENST00000380907.3	NP_683762.2
EXOC2	NM_018303.6	c.-43-18680G>C		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.404G>C	p.Arg135Pro	missense_variant	Exon 1 of 1	6	NM_148959.4	ENSP00000370293.2
EXOC2	ENST00000230449.9	c.-43-18680G>C		intron_variant	Intron 1 of 27	1	NM_018303.6	ENSP00000230449.4
EXOC2	ENST00000443083.5	c.-44+622G>C		intron_variant	Intron 3 of 5	3		ENSP00000406400.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1448606 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 719638

African (AFR) AF: 0.0000300 AC: 1 AN: 33280

American (AMR) AF: 0.00 AC: 0 AN: 44336

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25764

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00 AC: 0 AN: 85386

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47660

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1106960

Other (OTH) AF: 0.00 AC: 0 AN: 59958

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Apr 06, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.404G>C (p.R135P) alteration is located in exon 1 (coding exon 1) of the HUS1B gene. This alteration results from a G to C substitution at nucleotide position 404, causing the arginine (R) at amino acid position 135 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Benign	-0.086	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	9.3
DANN	Benign	0.71
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.93
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.034	N
LIST_S2	Benign	0.44	T
M_CAP	Benign	0.0029	T
MetaRNN	Uncertain	0.45	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	2.0	M
PhyloP100		-0.052
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.096
Sift	Benign	0.18	T
Sift4G	Benign	0.20	T
Polyphen		0.77	P
Vest4		0.30
MutPred		0.52		Loss of MoRF binding (P = 3e-04);
MVP		0.14
MPC		0.82
ClinPred		0.44	T
GERP RS		-0.35
Varity_R		0.91
gMVP		0.70
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1484409532; hg19: chr6-656541;