rs869025320

chr2-209775898-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001371986.1(UNC80):c.151C>T(p.Arg51Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: UNC80 NM_001371986.1 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 2.37

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-209775898-C-T is Pathogenic according to our data. Variant chr2-209775898-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 222017.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-209775898-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
UNC80	NM_001371986.1	c.151C>T	p.Arg51Ter	stop_gained	3/65	ENST00000673920.1
UNC80	NM_032504.2	c.151C>T	p.Arg51Ter	stop_gained	3/64
UNC80	NM_182587.4	c.151C>T	p.Arg51Ter	stop_gained	3/63

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
UNC80	ENST00000673920.1	c.151C>T	p.Arg51Ter	stop_gained	3/65		NM_001371986.1	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461352 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726956

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 02, 2022	Variant summary: UNC80 c.151C>T (p.Arg51X) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic in ClinVar and HGMD. The variant was absent in 251190 control chromosomes. c.151C>T has been reported in the literature in multiple homozygous individuals of a remotely related consanguineous Bedouin kindred, affected with Infantile Hypotonia With Psychomotor Retardation And Characteristic Facies 2 (Perez_2016). These data indicate that the variant is very likely to be associated with disease. Experimental evidence evaluating an impact on protein function, demonstrated the variant protein was not expressed in vitro (Perez_2016). A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jun 14, 2016	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	37
Dann	Uncertain	1.0
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.72
FATHMM_MKL	Uncertain	0.95	D
MutationTaster	Benign	1.0	A;A
Vest4		0.46
GERP RS		5.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs869025320; hg19: chr2-210640622; COSMIC: COSV55900986;