rs59504201

chr2-209995372-C-Gchr2-209995372-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

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. 13/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (24 hom., cov: 32)
  • Exomes 𝑓: 0.0013 (25 hom.)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.471

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]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, UNC80
• 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC80	NM_001371986.1	c.9752C>G	p.Thr3251Arg	missense_variant	65/65	ENST00000673920.1
UNC80	NM_032504.2	c.9554C>G	p.Thr3185Arg	missense_variant	64/64
UNC80	NM_182587.4	c.9482C>G	p.Thr3161Arg	missense_variant	63/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC80	ENST00000673920.1	c.9752C>G	p.Thr3251Arg	missense_variant	65/65		NM_001371986.1	A2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1637 AN: 152216 Hom.: 24 Cov.: 32

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

GnomAD3 exomes AF: 0.00276 AC: 436 AN: 157918 Hom.: 6 AF XY: 0.00209 AC XY: 174 AN XY: 83274

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 SAS exome AF: 0.000132

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.: 25 Cov.: 31 AF XY: 0.00116 AC XY: 801 AN XY: 690404

Gnomad4 AFR exome AF: 0.0365

Gnomad4 AMR exome AF: 0.00423

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000883

Gnomad4 FIN exome AF: 0.0000202

Gnomad4 NFE exome AF: 0.000216

Gnomad4 OTH exome AF: 0.00378

GnomAD4 genome AF: 0.0108 AC: 1643 AN: 152334 Hom.: 24 Cov.: 32 AF XY: 0.0103 AC XY: 770 AN XY: 74496

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00823

Gnomad4 ASJ AF: 0.00259

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000426

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00166 Hom.: 1

Bravo AF: 0.0127

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.0260 AC: 36

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00400 AC: 105

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Apr 19, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

UNC80-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 25, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 04, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.67
Cadd	Benign	7.6
Dann	Benign	0.91
DEOGEN2	Benign	0.044	T;.
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.76	T;T
MetaRNN	Benign	0.0024	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.29	T
PROVEAN	Benign	-0.74	N;N
REVEL	Benign	0.082
Sift	Benign	0.13	T;T
Sift4G	Uncertain	0.038	D;D
Polyphen		0.0	B;.
Vest4		0.061
MVP		0.067
MPC		0.36
ClinPred		0.00092	T
GERP RS		1.2
Varity_R		0.066
gMVP		0.19

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

LitVar

Other links and lift over

dbSNP: rs59504201; hg19: chr2-210860096;