2-209877990-G-A

Variant names:

• chr2-209877990-G-A
• rs187089611
• NM_001371986.1:c.3877G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001371986.1(UNC80):​c.3877G>A​(p.Glu1293Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 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. E1293Q) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.60
• 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.30812126).

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.3877G>A	p.Glu1293Lys	missense	Exon 24 of 65	NP_001358915.1
	UNC80	NM_032504.2		c.3883G>A	p.Glu1295Lys	missense	Exon 24 of 64	NP_115893.1
	UNC80	NM_182587.4		c.3868G>A	p.Glu1290Lys	missense	Exon 24 of 63	NP_872393.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.3877G>A	p.Glu1293Lys	missense	Exon 24 of 65	ENSP00000501211.1
	UNC80	ENST00000489023.5	TSL:1	n.1408G>A		non_coding_transcript_exon	Exon 10 of 37
	UNC80	ENST00000439458.5	TSL:5	c.3883G>A	p.Glu1295Lys	missense	Exon 24 of 64	ENSP00000391088.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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	Benign	-0.049	T
BayesDel_noAF	Benign	-0.31
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.31	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L
PhyloP100		9.6
PrimateAI	Uncertain	0.77	T
PROVEAN	Uncertain	-2.5	N
REVEL	Benign	0.21
Sift	Uncertain	0.017	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.73	P
Vest4		0.43
MutPred		0.34		Gain of ubiquitination at E1295 (P = 0.0075)
MVP		0.35
MPC		0.82
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.31
gMVP		0.72
Mutation Taster		=62/38	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: rs187089611; hg19: chr2-210742714; COSMIC: COSV55904794;