rs201312129

Positions:

chr2-209995487-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_001371986.1(UNC80):c.9867T>A(p.His3289Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000419 in 1,551,730 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H3289R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000042 ( 0 hom. )

Consequence

UNC80
NM_001371986.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 0.275

Variant links:

Genes affected

UNC80 (HGNC:26582): (unc-80 homolog, NALCN channel complex subunit) The protein encoded by this gene is a component of a voltage-independent 'leak' ion-channel complex, in which it performs essential functions, such as serving as a bridge between two other components (sodium leak channel non-selective and UNC79) and as a scaffold for Src kinases. Leak channels play an importnat role in establishment and maintenance of resting membrane potentials in neurons. Mutations in this gene are associated with congenital infantile encephalopathy, intellectual disability and growth issues. [provided by RefSeq, Aug 2016]

UNC80 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UNC80. . Gene score misZ 5.5319 (greater than the threshold 3.09). Trascript score misZ 4.9857 (greater than threshold 3.09). GenCC has associacion of gene with hypotonia, infantile, with psychomotor retardation and characteristic facies 2, hypotonia, infantile, with psychomotor retardation and characteristic facies.

BP4

Computational evidence support a benign effect (MetaRNN=0.13593432).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
UNC80	NM_001371986.1 linkuse as main transcript	c.9867T>A	p.His3289Gln	missense_variant	65/65	ENST00000673920.1
UNC80	NM_032504.2 linkuse as main transcript	c.9669T>A	p.His3223Gln	missense_variant	64/64
UNC80	NM_182587.4 linkuse as main transcript	c.9597T>A	p.His3199Gln	missense_variant	63/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC80	ENST00000673920.1 linkuse as main transcript	c.9867T>A	p.His3289Gln	missense_variant	65/65		NM_001371986.1	A2

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

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:

0.00

GnomAD3 exomes

AF:

0.0000127

AC:

AN:

157346

Hom.:

AF XY:

0.0000120

AC XY:

AN XY:

83212

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000164

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000422

AC:

AN:

1399538

Hom.:

Cov.:

AF XY:

0.0000391

AC XY:

AN XY:

690272

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000473

Gnomad4 OTH exome

AF:

0.0000689

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000982

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Aug 19, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 06, 2022	- -

not provided

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 07, 2024	This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 3223 of the UNC80 protein (p.His3223Gln). This variant is present in population databases (rs201312129, gnomAD 0.002%). This variant has not been reported in the literature in individuals affected with UNC80-related conditions. ClinVar contains an entry for this variant (Variation ID: 452020). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt UNC80 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Sep 22, 2017	The H3223Q variant in the UNC80 gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The H3223Q variant is not observed at a significant frequency in large population cohorts (Lek et al., 2016). The H3223Q variant is a semi-conservative amino acid substitution, which occurs at a position that is conserved across species. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret H3223Q as a variant of uncertain significance. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2022

The c.9669T>A (p.H3223Q) alteration is located in exon 64 (coding exon 64) of the UNC80 gene. This alteration results from a T to A substitution at nucleotide position 9669, causing the histidine (H) at amino acid position 3223 to be replaced by a glutamine (Q). 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

Benign

0.15

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.38

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.040

T;.

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.29

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.75

T;T

M_CAP

Benign

0.0043

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.97

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Uncertain

0.73

PROVEAN

Benign

-0.94

N;N

REVEL

Benign

0.15

Sift

Pathogenic

0.0

D;D

Sift4G

Pathogenic

0.0010

D;D

Polyphen

0.72

P;.

Vest4

0.50

MutPred

0.32

Loss of sheet (P = 0.0817);.;

MVP

0.18

MPC

0.33

ClinPred

0.17

GERP RS

-1.1

Varity_R

0.22

gMVP

0.30

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over