2-209772094-G-A

Position:

• chr2-209772094-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.22G>A​(p.Glu8Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,397,518 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

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=0.13257647).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC80	NM_001371986.1	c.22G>A	p.Glu8Lys	missense_variant	1/65	ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2	c.22G>A	p.Glu8Lys	missense_variant	1/64		NP_115893.1
UNC80	NM_182587.4	c.22G>A	p.Glu8Lys	missense_variant	1/63		NP_872393.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1	c.22G>A	p.Glu8Lys	missense_variant	1/65		NM_001371986.1	ENSP00000501211.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1397518 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689328

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: 0.00000278

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 19, 2024

The c.22G>A (p.E8K) alteration is located in exon 1 (coding exon 1) of the UNC80 gene. This alteration results from a G to A substitution at nucleotide position 22, causing the glutamic acid (E) at amino acid position 8 to be replaced by a lysine (K). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.16
FATHMM_MKL	Benign	0.29	N
LIST_S2	Uncertain	0.93	D;D
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L;L
MutationTaster	Benign	0.87	N;N
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.66	N;N
REVEL	Benign	0.061
Sift	Benign	0.090	T;T
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.88	P;.
Vest4		0.18
MutPred		0.25		Gain of MoRF binding (P = 2e-04);Gain of MoRF binding (P = 2e-04);
MVP		0.10
MPC		0.56
ClinPred		0.76	D
GERP RS		3.5
Varity_R		0.31
gMVP		0.53

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-210636818;