rs869025318

Positions:

• chr2-209820378-TA-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.2033del​(p.Asn678ThrfsTer15) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC80 NM_001371986.1 frameshift
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: -0.133

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 2-209820378-TA-T is Pathogenic according to our data. Variant chr2-209820378-TA-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 222012.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr2-209820378-TA-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC80	NM_001371986.1	c.2033del	p.Asn678ThrfsTer15	frameshift_variant	13/65	ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2	c.2033del	p.Asn678ThrfsTer15	frameshift_variant	13/64		NP_115893.1
UNC80	NM_182587.4	c.2033del	p.Asn678ThrfsTer15	frameshift_variant	13/63		NP_872393.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1	c.2033del	p.Asn678ThrfsTer15	frameshift_variant	13/65		NM_001371986.1	ENSP00000501211	A2
UNC80	ENST00000439458.5	c.2033del	p.Asn678ThrfsTer15	frameshift_variant	13/64	5		ENSP00000391088	P4
UNC80	ENST00000673951.1	c.2033del	p.Asn678ThrfsTer15	frameshift_variant	13/64			ENSP00000501012	A1
UNC80	ENST00000272845.10	c.2033del	p.Asn678ThrfsTer15	frameshift_variant	13/63	5		ENSP00000272845	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter	research	Lupski Lab, Baylor-Hopkins CMG, Baylor College of Medicine	Jan 07, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Apr 09, 2018	- -

Computational scores

Source: dbNSFP v4.3

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: rs869025318; hg19: chr2-210685102;