2-209772116-G-A

Position:

• chr2-209772116-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001371986.1(UNC80):​c.44G>A​(p.Gly15Asp) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.84

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), UNC80. . Gene score misZ 5.5319 (greater than the threshold 3.09). Trascript score misZ 4.9857 (greater than threshold 3.09). GenCC has associacion of gene with hypotonia, infantile, with psychomotor retardation and characteristic facies 2, hypotonia, infantile, with psychomotor retardation and characteristic facies.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2217797).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC80	NM_001371986.1	c.44G>A	p.Gly15Asp	missense_variant	1/65	ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2	c.44G>A	p.Gly15Asp	missense_variant	1/64		NP_115893.1
UNC80	NM_182587.4	c.44G>A	p.Gly15Asp	missense_variant	1/63		NP_872393.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1	c.44G>A	p.Gly15Asp	missense_variant	1/65		NM_001371986.1	ENSP00000501211.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1397140 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 689150

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Asia WGS AF: 0.000290 AC: 1 AN: 3460

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Mar 22, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Not Available"). This variant has not been reported in the literature in individuals affected with UNC80-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glycine with aspartic acid at codon 15 of the UNC80 protein (p.Gly15Asp). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Benign	0.96
DEOGEN2	Benign	0.028	T;.
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.082
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.83	T;T
M_CAP	Uncertain	0.25	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.84	L;L
MutationTaster	Benign	0.65	N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	1.1	N;N
REVEL	Benign	0.091
Sift	Benign	0.10	T;T
Sift4G	Uncertain	0.010	D;D
Polyphen		0.74	P;.
Vest4		0.41
MutPred		0.21		Gain of solvent accessibility (P = 0.0638);Gain of solvent accessibility (P = 0.0638);
MVP		0.26
MPC		1.1
ClinPred		0.63	D
GERP RS		3.3
Varity_R		0.23
gMVP		0.70

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

Publications

LitVar

Other links and lift over

dbSNP: rs1574377240; hg19: chr2-210636840;