rs61271372

chr2-209993421-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.9503C>T(p.Pro3168Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00231 in 1,551,362 control chromosomes in the GnomAD database, including 48 homozygotes. In-silico tool predicts 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. P3168A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.011 (23 hom., cov: 32)
  • Exomes 𝑓: 0.0014 (25 hom.)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.29

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=0.0032159388).
• BP6: Variant 2-209993421-C-T is Benign according to our data. Variant chr2-209993421-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 445867.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-209993421-C-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0108 (1651/152276) while in subpopulation AFR AF= 0.0349 (1451/41532). AF 95% confidence interval is 0.0334. There are 23 homozygotes in gnomad4. There are 777 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC80	NM_001371986.1	c.9503C>T	p.Pro3168Leu	missense_variant	63/65	ENST00000673920.1
UNC80	NM_032504.2	c.9305C>T	p.Pro3102Leu	missense_variant	62/64
UNC80	NM_182587.4	c.9233C>T	p.Pro3078Leu	missense_variant	61/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC80	ENST00000673920.1	c.9503C>T	p.Pro3168Leu	missense_variant	63/65		NM_001371986.1	A2

Frequencies

GnomAD3 genomes AF: 0.0108 AC: 1645 AN: 152158 Hom.: 23 Cov.: 32

Gnomad AFR AF: 0.0349

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00831

Gnomad ASJ AF: 0.00260

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000500

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00273 AC: 428 AN: 156506 Hom.: 5 AF XY: 0.00211 AC XY: 175 AN XY: 82934

Gnomad AFR exome AF: 0.0350

Gnomad AMR exome AF: 0.00329

Gnomad ASJ exome AF: 0.00176

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000220

Gnomad FIN exome AF: 0.0000594

Gnomad NFE exome AF: 0.000611

Gnomad OTH exome AF: 0.00250

GnomAD4 exome AF: 0.00138 AC: 1926 AN: 1399086 Hom.: 25 Cov.: 30 AF XY: 0.00121 AC XY: 834 AN XY: 690054

Gnomad4 AFR exome AF: 0.0364

Gnomad4 AMR exome AF: 0.00426

Gnomad4 ASJ exome AF: 0.00234

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000164

Gnomad4 FIN exome AF: 0.0000203

Gnomad4 NFE exome AF: 0.000271

Gnomad4 OTH exome AF: 0.00391

GnomAD4 genome AF: 0.0108 AC: 1651 AN: 152276 Hom.: 23 Cov.: 32 AF XY: 0.0104 AC XY: 777 AN XY: 74472

Gnomad4 AFR AF: 0.0349

Gnomad4 AMR AF: 0.00830

Gnomad4 ASJ AF: 0.00260

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000500

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00228 Hom.: 8

Bravo AF: 0.0128

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.0260 AC: 36

ESP6500EA AF: 0.000314 AC: 1

ExAC AF: 0.00402 AC: 103

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

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

UNC80-related disorder 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). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.32
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.056	T;.
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.40
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.95	D;D
MetaRNN	Benign	0.0032	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.55	N;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.10
Sift	Uncertain	0.0030	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.82	P;.
Vest4		0.46
MVP		0.41
MPC		1.1
ClinPred		0.027	T
GERP RS		5.7
Varity_R		0.11
gMVP		0.31

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: rs61271372; hg19: chr2-210858145;