NM_001371986.1:c.600+5G>C

Variant names:

• chr2-209777564-G-C
• rs116203254
• NM_001371986.1:c.600+5G>C

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.600+5G>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: UNC80 NM_001371986.1 splice_region, intron
• Scores: Splicing: ADA: 0.6904
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.81
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).

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.600+5G>C		splice_region intron	N/A	NP_001358915.1
	UNC80	NM_032504.2		c.600+5G>C		splice_region intron	N/A	NP_115893.1
	UNC80	NM_182587.4		c.600+5G>C		splice_region intron	N/A	NP_872393.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.600+5G>C		splice_region intron	N/A	ENSP00000501211.1
	UNC80	ENST00000478701.1	TSL:1	n.680+5G>C		splice_region intron	N/A
	UNC80	ENST00000439458.5	TSL:5	c.600+5G>C		splice_region intron	N/A	ENSP00000391088.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446618 Hom.: 0 Cov.: 31 AF XY: 0.00000139 AC XY: 1 AN XY: 717968

African (AFR) AF: 0.00 AC: 0 AN: 33056

American (AMR) AF: 0.00 AC: 0 AN: 43460

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24870

East Asian (EAS) AF: 0.00 AC: 0 AN: 39610

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83374

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52860

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5638

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1104076

Other (OTH) AF: 0.00 AC: 0 AN: 59674

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	21
DANN	Benign	0.88
PhyloP100		2.8

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.69
dbscSNV1_RF	Benign	0.60
SpliceAI score (max)		0.010		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: rs116203254; hg19: chr2-210642288;