Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371986.1(UNC80):c.9752C>G(p.Thr3251Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00225 in 1,552,182 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T3251A) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.011 ( 24 hom., cov: 32)

Exomes 𝑓: 0.0013 ( 25 hom. )

Consequence

UNC80
NM_001371986.1 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.471

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

hypotonia, infantile, with psychomotor retardation and characteristic facies 2
Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, ClinGen
hypotonia, infantile, with psychomotor retardation and characteristic facies
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

UNC80 links:

ENSG00000295428 (HGNC:):

ENSG00000295428 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.002413869).

BP6

Variant 2-209995372-C-G is Benign according to our data. Variant chr2-209995372-C-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 445362.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0108 (1643/152334) while in subpopulation AFR AF = 0.0349 (1450/41568). AF 95% confidence interval is 0.0334. There are 24 homozygotes in GnomAd4. There are 770 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 24 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371986.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UNC80	NM_001371986.1	MANE Select	c.9752C>G	p.Thr3251Arg	missense	Exon 65 of 65	NP_001358915.1
UNC80	NM_032504.2		c.9554C>G	p.Thr3185Arg	missense	Exon 64 of 64	NP_115893.1
UNC80	NM_182587.4		c.9482C>G	p.Thr3161Arg	missense	Exon 63 of 63	NP_872393.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
UNC80	ENST00000673920.1	MANE Select	c.9752C>G	p.Thr3251Arg	missense	Exon 65 of 65	ENSP00000501211.1
UNC80	ENST00000439458.5	TSL:5	c.9554C>G	p.Thr3185Arg	missense	Exon 64 of 64	ENSP00000391088.1
UNC80	ENST00000673951.2		c.9548C>G	p.Thr3183Arg	missense	Exon 64 of 64	ENSP00000501012.1

Frequencies

GnomAD3 genomes

AF:

0.0108

AC:

1637

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0348

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00824

Gnomad ASJ

AF:

0.00259

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000426

Gnomad OTH

AF:

0.0134

GnomAD2 exomes

AF:

0.00276

AC:

436

AN:

157918

AF XY:

0.00209

show subpopulations

Gnomad AFR exome

AF:

0.0352

Gnomad AMR exome

AF:

0.00327

Gnomad ASJ exome

AF:

0.00176

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000589

Gnomad NFE exome

AF:

0.000571

Gnomad OTH exome

AF:

0.00246

GnomAD4 exome

AF:

0.00132

AC:

1854

AN:

1399848

Hom.:

Cov.:

AF XY:

0.00116

AC XY:

801

AN XY:

690404

show subpopulations

African (AFR)

AF:

0.0365

AC:

1153

AN:

31600

American (AMR)

AF:

0.00423

AC:

151

AN:

35710

Ashkenazi Jewish (ASJ)

AF:

0.00234

AC:

AN:

25182

East Asian (EAS)

AF:

0.00

AC:

AN:

35738

South Asian (SAS)

AF:

0.0000883

AC:

AN:

79236

European-Finnish (FIN)

AF:

0.0000202

AC:

AN:

49478

Middle Eastern (MID)

AF:

0.00526

AC:

AN:

5704

European-Non Finnish (NFE)

AF:

0.000216

AC:

233

AN:

1079068

Other (OTH)

AF:

0.00378

AC:

220

AN:

58132

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

198

296

395

494

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0108

AC:

1643

AN:

152334

Hom.:

Cov.:

AF XY:

0.0103

AC XY:

770

AN XY:

74496

show subpopulations

African (AFR)

AF:

0.0349

AC:

1450

AN:

41568

American (AMR)

AF:

0.00823

AC:

126

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00259

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5194

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000426

AC:

AN:

68024

Other (OTH)

AF:

0.0132

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

158

236

315

394

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00166

Hom.:

Bravo

AF:

0.0127

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.0260

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00400

AC:

105

Asia WGS

AF:

0.00260

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (3)

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (1)

UNC80-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.67

CADD

Benign

7.6

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.044

Eigen

Benign

-0.90

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0024

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.55

PhyloP100

0.47

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.74

REVEL

Benign

0.082

Sift

Benign

0.13

Sift4G

Uncertain

0.038

Polyphen

0.0

Vest4

0.061

MVP

0.067

MPC

0.36

ClinPred

0.00092

GERP RS

1.2

Varity_R

0.066

gMVP

0.19

Mutation Taster

=99/1

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

rs59504201

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over