rs116203254

chr2-209777564-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001371986.1(UNC80):c.600+5G>A variant causes a splice donor 5th base, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00139 in 1,598,946 control chromosomes in the GnomAD database, including 28 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0074 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00076 (8 hom.)
• Consequence: UNC80 NM_001371986.1 splice_donor_5th_base, intron
• Scores: Splicing: ADA: 0.8241
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.81

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.42).
• BP6: Variant 2-209777564-G-A is Benign according to our data. Variant chr2-209777564-G-A is described in ClinVar as [Benign]. Clinvar id is 377285.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 = 0.0074 (1127/152334) while in subpopulation AFR AF= 0.0254 (1056/41578). AF 95% confidence interval is 0.0241. There are 20 homozygotes in gnomad4. There are 581 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC80	NM_001371986.1	c.600+5G>A		splice_donor_5th_base_variant, intron_variant		ENST00000673920.1
UNC80	NM_032504.2	c.600+5G>A		splice_donor_5th_base_variant, intron_variant
UNC80	NM_182587.4	c.600+5G>A		splice_donor_5th_base_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC80	ENST00000673920.1	c.600+5G>A		splice_donor_5th_base_variant, intron_variant			NM_001371986.1	A2

Frequencies

GnomAD3 genomes AF: 0.00741 AC: 1128 AN: 152216 Hom.: 20 Cov.: 33

Gnomad AFR AF: 0.0255

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

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: 0.000147

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00205 AC: 484 AN: 236034 Hom.: 8 AF XY: 0.00165 AC XY: 209 AN XY: 126942

Gnomad AFR exome AF: 0.0266

Gnomad AMR exome AF: 0.00103

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: 0.000140

Gnomad OTH exome AF: 0.00105

GnomAD4 exome AF: 0.000760 AC: 1100 AN: 1446612 Hom.: 8 Cov.: 31 AF XY: 0.000673 AC XY: 483 AN XY: 717966

Gnomad4 AFR exome AF: 0.0244

Gnomad4 AMR exome AF: 0.00122

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000240

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000129

Gnomad4 OTH exome AF: 0.00151

GnomAD4 genome AF: 0.00740 AC: 1127 AN: 152334 Hom.: 20 Cov.: 33 AF XY: 0.00780 AC XY: 581 AN XY: 74506

Gnomad4 AFR AF: 0.0254

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000147

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.00196 Hom.: 4

Bravo AF: 0.00810

Asia WGS AF: 0.00202 AC: 7 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 24, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

UNC80-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 21, 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Benign	0.83

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.82
dbscSNV1_RF	Benign	0.57
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: rs116203254; hg19: chr2-210642288;