2-209772171-G-A

Position:

• chr2-209772171-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_001371986.1(UNC80):​c.92+7G>A variant causes a splice region, intron change. The variant allele was found at a frequency of 0.00676 in 1,536,440 control chromosomes in the GnomAD database, including 58 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0045 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0070 (54 hom.)
• Consequence: UNC80 NM_001371986.1 splice_region, intron
• Scores: Splicing: ADA: 0.002059
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.98

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 Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 2-209772171-G-A is Benign according to our data. Variant chr2-209772171-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 710314.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-209772171-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00446 (676/151434) while in subpopulation NFE AF= 0.00777 (526/67702). AF 95% confidence interval is 0.00722. There are 4 homozygotes in gnomad4. There are 300 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
UNC80	NM_001371986.1	c.92+7G>A		splice_region_variant, intron_variant		ENST00000673920.1	NP_001358915.1
UNC80	NM_032504.2	c.92+7G>A		splice_region_variant, intron_variant			NP_115893.1
UNC80	NM_182587.4	c.92+7G>A		splice_region_variant, intron_variant			NP_872393.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
UNC80	ENST00000673920.1	c.92+7G>A		splice_region_variant, intron_variant			NM_001371986.1	ENSP00000501211.1

Frequencies

GnomAD3 genomes AF: 0.00445 AC: 674 AN: 151326 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00309

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00208

Gnomad FIN AF: 0.00355

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00777

Gnomad OTH AF: 0.00338

GnomAD3 exomes AF: 0.00397 AC: 528 AN: 133046 Hom.: 4 AF XY: 0.00403 AC XY: 291 AN XY: 72206

Gnomad AFR exome AF: 0.000971

Gnomad AMR exome AF: 0.00123

Gnomad ASJ exome AF: 0.000255

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00132

Gnomad FIN exome AF: 0.00444

Gnomad NFE exome AF: 0.00813

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00701 AC: 9714 AN: 1385006 Hom.: 54 Cov.: 31 AF XY: 0.00681 AC XY: 4655 AN XY: 683158

Gnomad4 AFR exome AF: 0.000962

Gnomad4 AMR exome AF: 0.00153

Gnomad4 ASJ exome AF: 0.000648

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00172

Gnomad4 FIN exome AF: 0.00430

Gnomad4 NFE exome AF: 0.00829

Gnomad4 OTH exome AF: 0.00662

GnomAD4 genome AF: 0.00446 AC: 676 AN: 151434 Hom.: 4 Cov.: 32 AF XY: 0.00406 AC XY: 300 AN XY: 73950

Gnomad4 AFR AF: 0.00113

Gnomad4 AMR AF: 0.00309

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00249

Gnomad4 FIN AF: 0.00355

Gnomad4 NFE AF: 0.00777

Gnomad4 OTH AF: 0.00334

Alfa AF: 0.00552 Hom.: 1

Bravo AF: 0.00447

Asia WGS AF: 0.000580 AC: 2 AN: 3462

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypotonia, infantile, with psychomotor retardation and characteristic facies 2 Benign:2

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 14, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jan 01, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2024	UNC80: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -

UNC80-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 25, 2020

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
CADD	Benign	17
DANN	Benign	0.96

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.054
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

LitVar

Other links and lift over

dbSNP: rs200211384; hg19: chr2-210636895;