rs201312129

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

2
2
15

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]

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 UniProt
UNC80NM_001371986.1 linkuse as main transcriptc.9867T>A p.His3289Gln missense_variant 65/65 ENST00000673920.1
UNC80NM_032504.2 linkuse as main transcriptc.9669T>A p.His3223Gln missense_variant 64/64
UNC80NM_182587.4 linkuse as main transcriptc.9597T>A p.His3199Gln missense_variant 63/63

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
UNC80ENST00000673920.1 linkuse as main transcriptc.9867T>A p.His3289Gln missense_variant 65/65 NM_001371986.1 A2

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152192
Hom.:
0
Cov.:
33
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:
2
AN:
157346
Hom.:
0
AF XY:
0.0000120
AC XY:
1
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:
59
AN:
1399538
Hom.:
0
Cov.:
31
AF XY:
0.0000391
AC XY:
27
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:
6
AN:
152192
Hom.:
0
Cov.:
33
AF XY:
0.0000134
AC XY:
1
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 submitterclinical testingFulgent Genetics, Fulgent GeneticsAug 19, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJan 06, 2022- -
not provided Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeJan 07, 2024This 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 submitterclinical testingGeneDxSep 22, 2017The 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 submitterclinical testingAmbry GeneticsSep 27, 2022The 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
T
BayesDel_noAF
Benign
-0.38
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Benign
0.040
T;.
Eigen
Benign
-0.32
Eigen_PC
Benign
-0.29
FATHMM_MKL
Benign
0.73
D
LIST_S2
Benign
0.75
T;T
M_CAP
Benign
0.0043
T
MetaRNN
Benign
0.14
T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.97
L;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Uncertain
0.73
T
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
T
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.

Other links and lift over

dbSNP: rs201312129; hg19: chr2-210860211; API