2-209813719-C-G

Variant names:

• chr2-209813719-C-G
• rs200659479
• NM_001371986.1:c.1078C>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001371986.1(UNC80):​c.1078C>G​(p.Arg360Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,514 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R360L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.842
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	NM_001371986.1	MANE Select	c.1078C>G	p.Arg360Gly	missense	Exon 8 of 65	NP_001358915.1
	UNC80	NM_032504.2		c.1078C>G	p.Arg360Gly	missense	Exon 8 of 64	NP_115893.1
	UNC80	NM_182587.4		c.1078C>G	p.Arg360Gly	missense	Exon 8 of 63	NP_872393.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.1078C>G	p.Arg360Gly	missense	Exon 8 of 65	ENSP00000501211.1
	UNC80	ENST00000439458.5	TSL:5	c.1078C>G	p.Arg360Gly	missense	Exon 8 of 64	ENSP00000391088.1
	UNC80	ENST00000673951.2		c.1078C>G	p.Arg360Gly	missense	Exon 8 of 64	ENSP00000501012.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399514 Hom.: 0 Cov.: 31 AF XY: 0.00000145 AC XY: 1 AN XY: 690272

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.00 AC: 0 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49336

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

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078990

Other (OTH) AF: 0.00 AC: 0 AN: 58030

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.48
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.069
Eigen_PC	Benign	-0.20
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.021	T
MetaRNN	Uncertain	0.48	T
MetaSVM	Benign	-0.63	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.84
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.6	D
REVEL	Uncertain	0.40
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.60
MutPred		0.51		Loss of stability (P = 0.0505)
MVP		0.21
MPC		1.0
ClinPred		0.96	D
GERP RS		-2.4
Varity_R		0.30
gMVP		0.53
Mutation Taster		=80/20	polymorphism

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: rs200659479; hg19: chr2-210678443;