rs868379708

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting

The NM_001371986.1(UNC80):c.9448C>T(p.Arg3150Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000309 in 1,551,756 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 (★★).

Frequency

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

Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

UNC80
NM_001371986.1 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 2.68

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 Likely_benign. Variant got -1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.11994293).

BS1

Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000314 (44/1399570) while in subpopulation MID AF= 0.000702 (4/5698). AF 95% confidence interval is 0.000239. There are 0 homozygotes in gnomad4_exome. There are 24 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
UNC80	NM_001371986.1 link	c.9448C>T	p.Arg3150Cys	missense_variant	Exon 63 of 65	ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2 link	c.9250C>T	p.Arg3084Cys	missense_variant	Exon 62 of 64		NP_115893.1	Q8N2C7-1
UNC80	NM_182587.4 link	c.9178C>T	p.Arg3060Cys	missense_variant	Exon 61 of 63		NP_872393.3	Q8N2C7-7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1 link	c.9448C>T	p.Arg3150Cys	missense_variant	Exon 63 of 65		NM_001371986.1	ENSP00000501211.1		A0A669KBC5

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000588

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000381

AC:

AN:

157664

Hom.:

AF XY:

0.0000240

AC XY:

AN XY:

83286

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000162

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:

0.0000163

Gnomad OTH exome

AF:

0.000224

GnomAD4 exome

AF:

0.0000314

AC:

AN:

1399570

Hom.:

Cov.:

AF XY:

0.0000348

AC XY:

AN XY:

690292

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000252

Gnomad4 FIN exome

AF:

0.0000202

Gnomad4 NFE exome

AF:

0.0000278

Gnomad4 OTH exome

AF:

0.0000344

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152186

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74352

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000588

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000823

Hom.:

Bravo

AF:

0.0000453

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2

Uncertain:2

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.9250C>T (p.R3084C) alteration is located in exon 62 (coding exon 62) of the UNC80 gene. This alteration results from a C to T substitution at nucleotide position 9250, causing the arginine (R) at amino acid position 3084 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jan 21, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 3084 of the UNC80 protein (p.Arg3084Cys). This variant is present in population databases (no rsID available, gnomAD 0.02%). 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: 548525). 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%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.34

BayesDel_noAF

Benign

-0.46

CADD

Uncertain

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.055

T;.

Eigen

Benign

-0.30

Eigen_PC

Benign

-0.15

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.91

D;D

M_CAP

Benign

0.016

MetaRNN

Benign

0.12

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.55

N;.

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.059

Sift

Benign

0.031

D;D

Sift4G

Pathogenic

0.0

D;D

Polyphen

0.022

B;.

Vest4

0.23

MVP

0.22

MPC

1.2

ClinPred

0.22

GERP RS

4.8

Varity_R

0.11

gMVP

0.35

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