rs144170692

Variant names:

• chr2-209839439-A-G
• rs144170692
• NM_001371986.1:c.3250+9A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PP3 BP6 BS1

The NM_032504.2(UNC80):​c.3256+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000366 in 1,551,908 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 predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: UNC80 NM_032504.2 splice_region, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 2.00
• 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: Likely_benign. The variant received -4 ACMG points.

• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BP6: Variant 2-209839439-A-G is Benign according to our data. Variant chr2-209839439-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 376940.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00188 (287/152278) while in subpopulation AFR AF = 0.00623 (259/41560). AF 95% confidence interval is 0.00561. There are 0 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032504.2. 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.3250+9A>G		intron	N/A	NP_001358915.1	A0A669KBC5
	UNC80	NM_032504.2		c.3256+3A>G		splice_region intron	N/A	NP_115893.1	Q8N2C7-1
	UNC80	NM_182587.4		c.3241+3A>G		splice_region intron	N/A	NP_872393.3	Q8N2C7-7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	UNC80	ENST00000673920.1	MANE Select	c.3250+9A>G		intron	N/A	ENSP00000501211.1	A0A669KBC5
	UNC80	ENST00000489023.5	TSL:1	n.781+3A>G		splice_region intron	N/A
	UNC80	ENST00000439458.5	TSL:5	c.3256+3A>G		splice_region intron	N/A	ENSP00000391088.1	Q8N2C7-1

Frequencies

GnomAD3 genomes AF: 0.00186 AC: 283 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00615

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.000420 AC: 66 AN: 157306 AF XY: 0.000337

Gnomad AFR exome AF: 0.00676

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000224

GnomAD4 exome AF: 0.000201 AC: 281 AN: 1399630 Hom.: 0 Cov.: 31 AF XY: 0.000187 AC XY: 129 AN XY: 690302

African (AFR) AF: 0.00560 AC: 177 AN: 31598

American (AMR) AF: 0.000532 AC: 19 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000505 AC: 4 AN: 79232

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49406

Middle Eastern (MID) AF: 0.000351 AC: 2 AN: 5700

European-Non Finnish (NFE) AF: 0.0000361 AC: 39 AN: 1078978

Other (OTH) AF: 0.000689 AC: 40 AN: 58090

GnomAD4 genome AF: 0.00188 AC: 287 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.00164 AC XY: 122 AN XY: 74460

African (AFR) AF: 0.00623 AC: 259 AN: 41560

American (AMR) AF: 0.00124 AC: 19 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68014

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00124 Hom.: 3

Bravo AF: 0.00232

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	1	-	Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 (1)
-	-	1	UNC80-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.20
CADD	Benign	18
DANN	Benign	0.96
PhyloP100		2.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.96
SpliceAI score (max)		0.55		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.55		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs144170692; hg19: chr2-210704163;