2-209872917-C-T

Variant names:

• chr2-209872917-C-T
• rs864321622
• NM_001371986.1:c.3787C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PVS1 PP5_Very_Strong

The NM_001371986.1(UNC80):​c.3787C>T​(p.Arg1263*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000005 in 1,399,344 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 Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: UNC80 NM_001371986.1 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.62
• Publications: 2 publications found

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]

UNC80 Gene-Disease associations (from GenCC):

• hypotonia, infantile, with psychomotor retardation and characteristic facies 2

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Illumina, ClinGen
• hypotonia, infantile, with psychomotor retardation and characteristic facies

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PP5: Variant 2-209872917-C-T is Pathogenic according to our data. Variant chr2-209872917-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 219188.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371986.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	NM_001371986.1	MANE Select	c.3787C>T	p.Arg1263*	stop_gained	Exon 23 of 65	NP_001358915.1
	UNC80	NM_032504.2		c.3793C>T	p.Arg1265*	stop_gained	Exon 23 of 64	NP_115893.1
	UNC80	NM_182587.4		c.3778C>T	p.Arg1260*	stop_gained	Exon 23 of 63	NP_872393.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.3787C>T	p.Arg1263*	stop_gained	Exon 23 of 65	ENSP00000501211.1
	UNC80	ENST00000489023.5	TSL:1	n.1318C>T		non_coding_transcript_exon	Exon 9 of 37
	UNC80	ENST00000439458.5	TSL:5	c.3793C>T	p.Arg1265*	stop_gained	Exon 23 of 64	ENSP00000391088.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000639 AC: 1 AN: 156454 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000500 AC: 7 AN: 1399344 Hom.: 0 Cov.: 31 AF XY: 0.00000435 AC XY: 3 AN XY: 690182

African (AFR) AF: 0.00 AC: 0 AN: 31594

American (AMR) AF: 0.0000280 AC: 1 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25180

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.00 AC: 0 AN: 79230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49276

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5698

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1078934

Other (OTH) AF: 0.00 AC: 0 AN: 57994

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000160 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (2)
1	-	-	Encephalopathy (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.54	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.82	D
PhyloP100		1.6
Vest4		0.57
GERP RS		4.7
Mutation Taster		=2/198	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs864321622; hg19: chr2-210737641;