chr2-209772094-G-A

Variant names:

• chr2-209772094-G-A
• rs1197659901
• NM_001371986.1:c.22G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E8Q) has been classified 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
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Illumina
• hypotonia, infantile, with psychomotor retardation and characteristic facies

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.13257647).

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.22G>A	p.Glu8Lys	missense	Exon 1 of 65	NP_001358915.1	A0A669KBC5
	UNC80	NM_032504.2		c.22G>A	p.Glu8Lys	missense	Exon 1 of 64	NP_115893.1	Q8N2C7-1
	UNC80	NM_182587.4		c.22G>A	p.Glu8Lys	missense	Exon 1 of 63	NP_872393.3	Q8N2C7-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.22G>A	p.Glu8Lys	missense	Exon 1 of 65	ENSP00000501211.1	A0A669KBC5
	UNC80	ENST00000478701.1	TSL:1	n.102G>A		non_coding_transcript_exon	Exon 1 of 8
	UNC80	ENST00000439458.5	TSL:5	c.22G>A	p.Glu8Lys	missense	Exon 1 of 64	ENSP00000391088.1	Q8N2C7-1

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

African (AFR) AF: 0.00 AC: 0 AN: 31500

American (AMR) AF: 0.00 AC: 0 AN: 35678

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25132

East Asian (EAS) AF: 0.00 AC: 0 AN: 35674

South Asian (SAS) AF: 0.00 AC: 0 AN: 79192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48692

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5302

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078442

Other (OTH) AF: 0.00 AC: 0 AN: 57906

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

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
M_CAP	Uncertain	0.086	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.0	L
PhyloP100		5.8
PrimateAI	Pathogenic	0.93	D
PROVEAN	Benign	-0.66	N
REVEL	Benign	0.061
Sift	Benign	0.090	T
Sift4G	Uncertain	0.0030	D
Polyphen		0.88	P
Vest4		0.18
MutPred		0.25		Gain of MoRF binding (P = 2e-04)
MVP		0.10
MPC		0.56
ClinPred		0.76	D
GERP RS		3.5
PromoterAI		-0.044	Neutral
Varity_R		0.31
gMVP		0.53
Mutation Taster		=74/26	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: rs1197659901; hg19: chr2-210636818; COSMIC: COSV107249976;