rs869025316

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001371986.1(UNC80):​c.5296C>T​(p.Pro1766Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,551,850 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000024 ( 0 hom. )

Consequence

UNC80
NM_001371986.1 missense

Scores

8
6
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:3

Conservation

PhyloP100: 7.91
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 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
UNC80NM_001371986.1 linkc.5296C>T p.Pro1766Ser missense_variant Exon 33 of 65 ENST00000673920.1 NP_001358915.1
UNC80NM_032504.2 linkc.5098C>T p.Pro1700Ser missense_variant Exon 32 of 64 NP_115893.1 Q8N2C7-1
UNC80NM_182587.4 linkc.5083C>T p.Pro1695Ser missense_variant Exon 32 of 63 NP_872393.3 Q8N2C7-7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
UNC80ENST00000673920.1 linkc.5296C>T p.Pro1766Ser missense_variant Exon 33 of 65 NM_001371986.1 ENSP00000501211.1 A0A669KBC5

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152158
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.000864
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:
0.0000380
AC:
6
AN:
157842
Hom.:
0
AF XY:
0.0000360
AC XY:
3
AN XY:
83352
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000470
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000439
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000163
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000243
AC:
34
AN:
1399692
Hom.:
0
Cov.:
31
AF XY:
0.0000174
AC XY:
12
AN XY:
690338
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.000834
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000379
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000556
Gnomad4 OTH exome
AF:
0.0000344
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152158
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.000864
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
Alfa
AF:
0.0000450
Hom.:
0
Bravo
AF:
0.0000302

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Pathogenic:2Uncertain:3
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 Pathogenic:2
Jan 07, 2016
Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine
Significance: Likely pathogenic
Review Status: criteria provided, single submitter
Collection Method: research

- -

Mar 29, 2016
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Uncertain:2
Jul 06, 2020
GeneDx
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Published functional studies suggest this variant has a damaging effect on NALCN channel currents (Stray-Pedersen et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26708751, 31589614) -

Oct 05, 2022
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Experimental studies have shown that this missense change affects UNC80 function (PMID: 26708751). 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. ClinVar contains an entry for this variant (Variation ID: 222010). This missense change has been observed in individual(s) with UNC80-related conditions (PMID: 26708751). This variant is present in population databases (no rsID available, gnomAD 0.05%). This sequence change replaces proline with serine at codon 1700 of the UNC80 protein (p.Pro1700Ser). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and serine. 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. -

not specified Uncertain:1
Jun 20, 2024
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Variant summary: UNC80 c.5098C>T (p.Pro1700Ser) results in a non-conservative amino acid change located in the Protein UNC80, central region (IPR045852) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.8e-05 in 157842 control chromosomes. c.5098C>T has been reported in the literature in at-least one individual affected with persistent hypotonia, encephalopathy, growth failure, and severe intellectual disability (example: Stray-Pedersen_2016). These data indicate that the variant may be associated with disease. At least one publication reports experimental evidence evaluating an impact on protein function. The most pronounced variant effect results in a damaging effect on NALCN channel currents (Stray-Pedersen _2016). The following publication has been ascertained in the context of this evaluation (PMID: 26708751). ClinVar contains an entry for this variant (Variation ID: 222010). Based on the evidence outlined above, the variant was classified as VUS-possibly pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.76
BayesDel_addAF
Uncertain
0.16
D
BayesDel_noAF
Uncertain
0.12
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.28
T;.
Eigen
Pathogenic
0.78
Eigen_PC
Pathogenic
0.77
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D
M_CAP
Benign
0.019
T
MetaRNN
Uncertain
0.74
D;D
MetaSVM
Benign
-0.61
T
MutationAssessor
Benign
1.6
L;.
PrimateAI
Pathogenic
0.84
D
PROVEAN
Pathogenic
-7.4
D;D
REVEL
Uncertain
0.42
Sift
Uncertain
0.0030
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;.
Vest4
0.93
MutPred
0.28
Loss of catalytic residue at P1700 (P = 0.0141);.;
MVP
0.37
MPC
1.1
ClinPred
0.92
D
GERP RS
5.3
Varity_R
0.68
gMVP
0.78

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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: rs869025316; hg19: chr2-210783340; API