chr2-209772154-C-T

Variant names:

• chr2-209772154-C-T
• rs1282118966
• NM_001371986.1:c.82C>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001371986.1(UNC80):​c.82C>T​(p.Arg28Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000718 in 1,393,468 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R28R) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: UNC80 NM_001371986.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• 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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.895

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.82C>T	p.Arg28Trp	missense	Exon 1 of 65	NP_001358915.1	A0A669KBC5
	UNC80	NM_032504.2		c.82C>T	p.Arg28Trp	missense	Exon 1 of 64	NP_115893.1	Q8N2C7-1
	UNC80	NM_182587.4		c.82C>T	p.Arg28Trp	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.82C>T	p.Arg28Trp	missense	Exon 1 of 65	ENSP00000501211.1	A0A669KBC5
	UNC80	ENST00000478701.1	TSL:1	n.162C>T		non_coding_transcript_exon	Exon 1 of 8
	UNC80	ENST00000439458.5	TSL:5	c.82C>T	p.Arg28Trp	missense	Exon 1 of 64	ENSP00000391088.1	Q8N2C7-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1393468 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 687336

African (AFR) AF: 0.00 AC: 0 AN: 30966

American (AMR) AF: 0.00 AC: 0 AN: 35568

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25010

East Asian (EAS) AF: 0.00 AC: 0 AN: 35318

South Asian (SAS) AF: 0.00 AC: 0 AN: 79030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4644

European-Non Finnish (NFE) AF: 9.29e-7 AC: 1 AN: 1076788

Other (OTH) AF: 0.00 AC: 0 AN: 57660

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.10
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.22
Eigen_PC	Benign	0.16
FATHMM_MKL	Benign	0.11	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.82	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		2.2
PrimateAI	Pathogenic	0.94	D
PROVEAN	Uncertain	-4.0	D
REVEL	Uncertain	0.47
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.73		Loss of MoRF binding (P = 0.0375)
MVP		0.28
MPC		0.99
ClinPred		1.0	D
GERP RS		2.2
PromoterAI		-0.047	Neutral
Varity_R		0.79
gMVP		0.84
Mutation Taster		=72/28	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: rs1282118966; hg19: chr2-210636878;